Mild Rh(III)-catalyzed C-H activation and annulation with alkyne MIDA boronates: Short, efficient synthesis of heterocyclic boronic acid derivatives

Article abstract of DOI:10.1021/ja310153v

Taking advantage of Rh(III)-catalyzed C-H activation reactions, we have developed a mild, short, and efficient method for the synthesis of bench-stable 3-isoquinolone MIDA boronates. The reaction is practical and scalable. The product formed has been applied in the Suzuki-Miyaura reaction with high efficiency. This strategy has also been successfully expanded to the synthesis of MIDA boronate functionalized heterocycles such as isoquinoline, pyrrole, and indole.

Full text of DOI:10.1021/ja310153v

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Communication
Mild Rhodium(III)-Catalyzed C–H Activation and Annulation
with Alkyne MIDA Boronates: Short and Efficient
Synthesis of Heterocyclic Boronic Acid Derivatives
Honggen Wang, Christoph Grohmann, Corinna Nimphius, and Frank Glorius
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 13 Nov 2012
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Mild Rhodium(III)-Catalyzed C–H Activation and Annulation
with Alkyne MIDA Boronates: Short and Efficient Synthesis of
Heterocyclic Boronic Acid Derivatives
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Honggen Wang, Christoph Grohmann, Corinna Nimphius, and Frank Glorius*
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstrasse 40, 48149 Münster, Germany
Supporting Information Placeholder
Scheme 1. Heterocyclic Boron Reagent Synthesis
ABSTRACT: Taking advantage of Rh(III)-catalyzed C–H acti-
vation reactions, we have developed a mild, short and efficient
method for the synthesis of bench-stable 3-isoquinolone MIDA
boronates. The reaction is practical and scalable. The product
formed has been applied in the Suzuki-Miyaura reaction with high
efficiency. This strategy has also been successfully expanded to
the synthesis of MIDA boronate functionalized heterocycles such
as isoquinoline, pyrrole and indole.
Organoboron compounds are among the most important and
valuable building blocks in organic synthesis due to their versatili-
ty in cross-coupling reactions to construct various carbon-carbon,
carbon-oxygen, and carbon-nitrogen bonds.1 However, in contrast
to the versatility of phenyl boronic acid and its derivatives, the
application of heterocyclic boron reagents, especially those where
boron is located adjacent to the ring heteroatom, frequently en-
counter a lot of problems.2 This is due to: 1) their inherent insta-
bility, which makes the purification and long term storage diffi-
cult; 2) their inefficiency in cross-coupling reactions; and 3) the
lack of efficient methods for their preparation. This is demonstrat-
ed by the striking fact that 3-isoquinolone3 and 3-isoquinoline4
boron reagents have seldom been utilized for synthesis, even
though these two skeletons are undoubtedly important in natural
products and pharmaceutical agents.
Additionally, the MIDA boronates are capable to undergo effi-
cient Suzuki-Hiyama coupling reactions under a controlled slow-
release strategy.11 On the other hand, we have been focusing on
Rh(III)-catalyzed C–H functionalization reactions under mild
reaction conditions.12-14 We thus reasoned that alkyne MIDA
boronates would be compatible with the mild reaction conditions,
thereby delivering interesting borylated heterocycles.15 Herein, we
report that 3-isoquinolone MIDA boronates can efficiently be
Typically, the synthesis of heterocyclic boron reagents relies
heavily on borylation of the metalated heterocycles.2a,5 The requi-
site prefunctionalization on a preformed heterocycle and the low
functional group tolerance dramatically limit their applications.
constructed by
a
Rh(III)-catalyzed annulation of N-
(pivaloyloxy)benzamides8s,13 and alkyne MIDA boronates. Fur-
thermore, this concept was successfully extended to the synthesis
of three other types of privileged B-containing N-heterocycles.
The past years have witnessed considerable progress in the field
of transition metal catalyzed C–H functionalization reactions.6
Notably, rhodium(III)-catalyzed C–H activation7 followed by
annulation reaction with alkynes has been frequently used as a
powerful tool to construct various heterocycles.8 Nevertheless,
there are still limitations: For example, most of these methods
suffer from harsh reaction conditions. In addition, the formation
of a single specific product, without valuable handle (for instance,
halogen or boron) on the newly-formed ring for further derivatiza-
tion restricts their applicability to a large extent. However, in
medicinal chemistry wherein complexity and diversity based on a
core molecule is crucial for lead discovery and optimization, the
construction of heterocycles9 with a versatile handle for divergent
synthesis is highly desirable for rapid library development.
We commenced our study by investigating the coupling reac-
tion of 1a and ethynyl MIDA boronate 2a.16 Unfortunately, under
the reaction conditions reported previously by others8s and us13,
the desired product 3a was not observed (Table 1, entry 1). Real-
izing that MIDA boronates would be labile in basic alcoholic
solution,17 we turned our efforts to the screening of different
solvents. Indeed, acetonitrile was found to be an ideal solvent for
this transformation, delivering borylated isoquinolone 3a in 50%
yield with complete regioselectivity, the boron being attached
next to the heteroatom nitrogen (entry 2). Notably, 3a is a bench-
stable off-white solid, which can be easily purified by silica gel
chromatography without detectable decomposition. Replacing
CsOAc with CsOPiv resulted in a higher yield of 63% (entry 3).
An attempt to lower the base loading failed as a decreased yield of
48% was obtained (entry 4). Interestingly, extensive experimenta-
tion revealed that the addition of a sub-stoichiometric amount of
Cu(OAc)2 facilitated this reaction, improving the yield to 85%
(entry 6). The dimerization of 2a caused by Cu(OAc)2 was not
In the past years, the group of Burke introduced MIDA (N-
methyliminodiacetic acid) boronates as a stable, reliable surrogate
of boronic acids, which renders the late stage modification of
organoboron reagents feasible under various reaction conditions.10
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significant since a slight excess of ethynyl MIDA boronate (1.2
Table 2. Rh(III)-catalyzed C–H Coupling of N-
(pivaloyloxy)benzamides with Ethynyl MIDA Boronatea
equivalents) was sufficient to ensure a high yield.18 The role of
Cu(OAc)2 is unknown at this point.19 The use of AgOAc or
CuII(2-ethylhexanoate)220 was proven to be less efficient (entry 5
and 7). Furthermore, the failure of boronate 2b (entry 8), leading
only to protodeboronated isoquinolin-1(2H)-one product in 9%
yield, was testimony for the importance of the MIDA boronate
group.
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Table 1. Reaction Optimizationa
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Entry
Base (equiv)
Additive
(mol%)
Solvent
Yieldb
(%)
2
1
2
3
4
5
6
CsOAc (2.0)
CsOAc (2.0)
CsOPiv (2.0)
CsOPiv (1.0)
-
-
-
-
MeOH
CH3CN
CH3CN
CH3CN
0%
2a
2a
2a
2a
2a
50%
63%
48%
45%
CsOPiv (2.0) AgOAc (50) CH3CN
b
c
a1 (0.2 mmol), 2a (0.24 mmol). 40 °C was used. Ratio of re-
gioisomers (major isomer shown).
2a CsOPiv (2.0) Cu(OAc)2
(40)
CH3CN 85%
Cu(2-ethyl
hexanoate)2
(40)
7
8
CsOPiv (2.0)
CH3CN
CH3CN
74%
0%c
2a
were installed in the same molecule, provide an ideal platform
for iterative cross-coupling and orthogonal functionalization.22
Unfortunately, attempts to utilize internal alkyne MIDA boronates
2c and 2d failed. Giving the fact that internal alkynes are predom-
inantly used in C–H functionalization reactions8,23, we presumed
that the presence of the bulky MIDA boronate may impart a sig-
nificant steric demand thus rendering this reaction sensitive to
additional steric interference.
CsOPiv (2.0) Cu(OAc)2
2b
(40)
Reaction Conditions: a1a (0.2 mmol), 2 (0.24 mmol, 1.2
equiv), [RhCp*Cl2]2 (2.5 mol%), solvent (2 mL), rt, 16 h. I-
solated yields. Yield of the corresponding borylated product;
instead, 9% of the protodeboronated isoquinolin-1(2H)-one were
b
c
It should be mentioned that the MIDA boronate within the
products is a valuable synthetic handle, being transformable to
various functionalities.10 In order to elucidate this, Suzuki-
Miyaura reactions were conducted under slow release reaction
formed.
With the optimized conditions in hand, we sought to investigate
the generality of this reaction (Table 2). Many substituents regard-
less of electron-donating or electron-withdrawing properties on
the aromatic ring were well tolerated, providing the products in
moderate to excellent yields (45-95%). It should be mentioned
that electron-withdrawing groups somewhat retarded the reaction.
o
However, by slightly elevating the reaction temperature to 40 C,
these reactions underwent smoothly. Importantly, functional
groups like methoxy, fluoro, chloro, bromo, iodo, trifluoromethyl,
ester, cyano, and nitro are commonly encountered in organic
synthesis, thus giving ample opportunity for further elaboration.
When meta-substituted substrates were applied, good regioselec-
tivities favoring activation of the less hindered C–H bond were
usually observed (3n-p). However, the m-OMe substrate was an
exception as a 1:1 ratio of inseparable regioisomers was ob-
tained(3q).21 Gratifyingly, several heterocyclic derivatives like
furan, thiophene and indole were suitable substrates for this trans-
formation, delivering the cyclization products in good to quantita-
tive yields (3r, 3s, 3t). The C–H activation took place exclusively
at the α position of the furan when 1r was subjected. Notably,
products 3g, 3h, 3i and 3p, wherein halogen and boron
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conditions.11 We were pleased to observe the smooth formation
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of arylation products 4, with differently substituted aryl and het-
eroaryl bromides being well tolerated (eq 1).24 In line with green
chemistry principles, a one-pot C–H functionalization/Suzuki-
Miyaura coupling sequence was also realized and a low but prom-
ising overall yield of 35% was obtained (eq 2).25 In addition, the
reaction is scalable and practical since equal efficiency was ob-
served when the reaction was performed on a gram scale (eq 3).
Consistent with previous observations,8s,13 a large primary ki-
netic isotope effect value of 8.0 was obtained (eq 4), indicating
the C–H activation to be involved in the rate-limiting step.26 The
observed insertion outcome would be rationalized by the more
pronounced steric interaction of the boron motif with the aryl ring
than that with the metal center (Scheme 2). However, previous
observations have revealed the larger substituent is preferentially
positioned far away from the bulky Cp* ligand when electronical-
ly similar disubstituted alkynes were used.8c,g-i Therefore, it is
more reasonable to assume that the electronic bias of the ethynyl
MIDA boronate governs the regioselectivity.27 Reductive elimina-
tion delivers the product and concomitantly regenerates the
Rh(III) catalyst.28
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Reaction conditions: (a) [RhCp*Cl2]2 (10 mol%), CsOAc or
K2CO3 (2.0 equiv), CH3CN, 60 oC, 18 h. (b) [RhCp*Cl2]2 (5
mol%), Cu(OAc)2 (2.2 equiv), acetone, 60 oC, 18 h. (c)
[Cp*Rh(MeCN)3][SbF6]2 (10 mol%), Cu(OAc)2 (2.2 equiv),
acetone, 80 oC, 18 h. (d) Pd(OAc)2 (10 mol%), SPhos (20 mol%),
bromobenzene, K3PO4, THF/H2O, 60 oC, 18 h.
Scheme 2. Mechanistic Proposal
In summary, by using C–H activation/alkyne MIDA boronate
annulation strategy under the catalysis of Rh(III), we have identi-
fied a new method for the efficient, short and straightforward
access to four important classes of 2-heterocyclic MIDA boro-
nates: isoquinolone, isoquinoline, pyrrole, and indole. The boron
substituent attached can serve as a synthetically valuable handle
for further transformations, as demonstrated by successful Suzuki-
Miyaura coupling reactions. Given the prevalence of these hetero-
cycles in pharmaceuticals, natural products and materials, and the
inherent challenges to access their corresponding 2-heterocyclic
boron reagents by other methods, we believe this methodology
will find broad applications.
ASSOCIATED CONTENT
Supporting Information
To further highlight the versatility of this strategy, we next
turned our attention to the synthesis of MIDA boronates of other
privileged heterocycles. The results turned out to be extremely
encouraging (Scheme 3). For example, treatment of oxime 5 with
both terminal and internal alkyne MIDA boronates under Rh(III)
catalysis gave the corresponding cyclized isoquinoline products 8
bearing a boron handle in modest yields. Importantly, the success
of using internal alkyne MIDA boronate as a coupling partner
make the products highly functionalized and diversified, even
though a low regioselectivitiy (1:1) is observed when p-
tolylethynyl MIDA boronate 2d29 was applied. Furthermore, by a
vinylic C–H activation/internal alkyne MIDA boronate annulation
sequence, we were able to construct borylated pyrroles 930 with
good efficiency.31 Interestingly, the coupling of 2d resulted in a
reverse of regioselectivity, giving 3-borylated pyrrole 9b as major
product.32 Again, the Suzuki-Miyaura coupling of 9a with bromo-
benzene delivered the arylated pyrrole 11 in excellent yield, with
the concomitant removal of acetyl group. The use of stoichio-
metric amounts of external oxidant Cu(OAc)2 probably prohibits
the coupling of terminal ethynyl MIDA in this case.18 Similarly,
the formation of indole MIDA boronates 10 was also achieved by
the C-H functionalization of an urea protected aniline 7.33 10 was
transformed to the corresponding 2-phenylindole 12 in reasonable
yield.
Detailed experimental procedures; characterization data of all new
compounds. This material is available free of charge via the Inter-
net at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
glorius@uni-muenster.de
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Generous financial support by the European Research Council
under the European Community's Seventh Framework Program
(FP7 2007-2013)/ERC Grant agreement no 25936, the DFG
(IRTG Münster-Nagoya) and SusChemSys (co-funded by the
European Regional Development Fund (ERDF) (2007-2013)) is
gratefully acknowledged. The research of F.G. has been supported
by the Alfried Krupp Prize for Young University Teachers of the
Alfried Krupp von Bohlen und Halbach Foundation.
Scheme 3. Synthesis of Other Heterocyclic MIDA Boro-
nates
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Org. Lett. 2012, 14, 27.
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Int. Ed. 2009, 48, 3565. (i) Wang, C.; Glorius, F. Angew. Chem., Int. Ed.
2009, 48, 5240.
(23) For C-H functionalization using terminal alkynes as coupling part-
ner, see ref 8s and Martin, R. M.; Bergman, R. G.; Ellman, J. A. J. Org.
Chem. 2012, 77, 2501.
(24) Guimond and Fagnou reported the use of alkyl-substituted termi-
nal alkyne delivering 3-alkyl monosubstituted isoquinolone in their reac-
tion. However, the use of phenylacetylene gave no corresponding desired
product. See ref 8s for detail.
(25) Control experiments indicate that remaining Cu(OAc)2 and
CsOPiv are the main factors responsible for the low efficiency of the
Suzuki-Miyaura coupling in this one-pot process. See SI for more details.
(26) Simmons, E. M.; Hartwig, J. F. Angew. Chem., Int. Ed. 2012, 51,
3066.
(27) Li, L.; Jiao, Y. Z.; Brennessel, W. W.; Jones, W. D.
Organometallics 2010, 29, 4593.
(28) Xu, L.; Zhu, Q.; Huang, G.; Cheng, B.; Xia, Y. J. Org. Chem.
2012, 77, 3017.
(29) 2d was synthesized efficiently by a Sonogashira coupling reaction,
see supporting information for details.
(30) For recent applications: (a) Smithen, D. A.; Baker, A. E. G.; Off-
man, M.; Crawford, S. M.; Cameron, T. S.; Thompson, A. J. Org. Chem.
2012, 77, 3439. (b) Asano, S.; Kamioka, S.; Isobe, Y. Tetrahedron 2012,
68, 272.
(31) Similar to the use of boronate 2b (Table 1, entry 8), the coupling
of 1-heptynylboronic acid pinacol ester with 6 under otherwise identical
reaction conditions gave no corresponding product. Instead, the dimeriza-
tion of the alkynylboronate resulted in the formation of the 1,3-diyne,
together with the recovery of 6.
(32) For a similar switch of regioselectivity when TMS substituted al-
kynes were used as coupling partners, see ref 8g.
(33) For recent applications: (a) Reilly, M. K.; Rychnovsky, S. D. Syn-
lett 2011, 2392. (b) Thakur, A.; Zhang, K.; Louie, J. Chem. Commun.
2012, 48, 203.
(10) (a) Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2007, 129, 6716.
(b) Lee, S. J.; Gray, K. C.; Paek, J. S.; Burke, M. D. J. Am. Chem. Soc.
2008, 130, 466. (c) Uno, B. E.; Gillis, E. P.; Burke, M. D. Tetrahedron
2009, 65, 3130. (d) Ballmer, S. G.; Gillis, E. P.; Burke, M. D. Org. Synth.
2009, 86, 344. (e) Gillis, E. P.; Burke, M. D. Aldrichimica Acta 2009, 42,
17. (f) Lee, S. J.; Anderson, T. M.; Burke, M. D. Angew. Chem., Int. Ed.
2010, 49, 8860. (g) Dick, G. R.; Woerly, E. M.; Burke, M. D. Angew.
Chem., Int. Ed. 2012, 51, 2667. For another class of protected boron
reagents, see: (h) Noguchi, H.; Hojo, K.; Suginome, M. J. Am. Chem. Soc.
2007, 129, 758.
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Heterocycle Formation/Boron Incorporation
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+ mild and efficient C-H activation
+ bench-stable products
+ highly efficient follow-up cross-couplings
O
O
&
3 other classes of
borylated heterocycles
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