A telescoped Knochel-Hauser/Kumada-Corriu coupling strategy to functionalized aromatic heterocycles

Article abstract of DOI:10.1016/j.tetlet.2018.11.014

The direct application of Knochel-Hauser derivative arylmagnesium halides in Kumada-Corriu couplings is described. By utilizing the in situ-generated Grignard reagents, the transmetalation with stoichiometric zinc salts to known Negishi coupling conditions is avoided, thereby streamlining the transformation. Several aromatic hetereocycles participate in the deprotonation and couple with a variety of phenyl iodides and bromides in isolated yields up to 81%. The parent system is demonstrated on 6 g scale with 79% yield, and monitored via ReactIR to show the stability of the Grignard and progression of the deprotonation/C–C coupling reaction.

Full text of DOI:10.1016/j.tetlet.2018.11.014

Accepted Manuscript
A Telescoped Knochel-Hauser / Kumada-Corriu Coupling Strategy to Func-
tionalized Aromatic Heterocycles
Kyle Clagg, Sara Hold, Archana Kumar, Stefan G. Koenig, Remy Angelaud
PII:
S0040-4039(18)31330-3
https://doi.org/10.1016/j.tetlet.2018.11.014
TETL 50399
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Reference:
Tetrahedron Letters
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29 October 2018
5 November 2018
Please cite this article as: Clagg, K., Hold, S., Kumar, A., Koenig, S.G., Angelaud, R., A Telescoped Knochel-
Hauser / Kumada-Corriu Coupling Strategy to Functionalized Aromatic Heterocycles, Tetrahedron Letters (2018),
doi: https://doi.org/10.1016/j.tetlet.2018.11.014
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Tetrahedron Letters
A Telescoped Knochel-Hauser / Kumada-Corriu Coupling Strategy to Functionalized
Aromatic Heterocycles
Kyle Clagg, a Sara Hold, a Archana Kumar,b Stefan G. Koeniga,* and Remy Angelauda
aSmall Molecule Process Chemistry, Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA
bSmall Molecule Analytical Chemistry and Quality Control, Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The direct application of Knochel-Hauser derivative arylmagnesium halides in Kumada-Corriu
couplings is described. By utilizing the in situ-generated Grignard reagents, the transmetalation
with stoichiometric zinc salts to known Negishi coupling conditions is avoided, thereby
streamlining the transformation. Several aromatic hetereocycles participate in the deprotonation
and couple with a variety of phenyl iodides and bromides in isolated yields up to 81%. The
parent system is demonstrated on 6 g scale with 79% yield, and monitored via ReactIR to show
the stability of the Grignard and progression of the deprotonation / C-C coupling reaction.
Available online
Keywords:
Kumada-Corriu cross-coupling
Knochel-Hauser base
C-H functionalization
Sustainability
2009 Elsevier Ltd. All rights reserved.
ReactIR
1. Introduction
coupling methodology with a series of diverse heterocycles. We
include a detailed study of the parent reaction by ReactIR to
Selective substitution of heterocycles is of great importance
for the construction of increasingly complex molecular targets,
particularly in the pharmaceutical industry. Recent years have
seen a bounty of work exploring methods of C-H bond
functionalization to replace the need for pre-functionalized
substrates. These C-H transformations have been guided by two
modes: innate reactivity or under guided conditions.1 In cases
where innate reactivity does not permit the desired
transformation, other chemistry can allow for a different path to
achieve the functionalization objective. To this end, directed
ortho metalation approaches have enabled the selective
deprotonation of arene substrates to facilitate subsequent
substitution. More recently, pioneering reagents have provided
access to reactive intermediates containing sensitive functionality
under mild conditions via kinetic deprotonations.
evaluate the key attributes of the stepwise transformation.
2. Results / Discussion
Scheme 1. C-C sp2-sp2 coupling of interest
While investigating a pipeline project, we came across the
need to functionalize fused pyrazolopiperidine intermediate 1 in
the 3-position. During the course of our research, we found that
TMPMgCl•LiCl was uniquely suited for selective deprotonation
and later derivatization with an electrophile quench under
ambient temperature.6 Curious about the further reactivity of 1,7
we subsequently reproduced literature Negishi conditions with a
Pd catalyst and iodobenzene, following transmetalation with
ZnCl2 (Scheme 1, 62 A% 3 by HPLC via intermediate 2b).
When we probed whether the original organomagnesium chloride
(2a) would also react with PhI in the presence of a catalyst, we
were surprised that this coupling worked equally well (68 A% 3).
After appropriate work-up conditions were identified (see
Supporting Information) to deal with the suspended Mg salts, we
isolated the phenyl-substituted derivative in good yield (57%
isolated yield from 2a).
Over the years, Knochel and others have introduced lithium
chloride-attenuated reagents that facilitate selective metalation,
deprotonation or nucleophilic additions.2 The magnesium base
derivatives have been harnessed for selective deprotonations and
functionalization via ensuing treatment with electrophilic species.
In some cases, the reactive intermediates were steered into more
sophisticated C-C bond formation reactions via a palladium-
catalyzed Negishi protocol following transmetalation of the
organomagnesium halides with zinc salts.3 However, only select
reports with thiophene substrates have described a C-C coupling
sequence with the heteroarylmagnesium species4 in a direct
coupling, with the work focused not on discrete molecular
products but rather polymerization of these heterocycles.5 Herein
we describe the direct application of Knochel-Hauser base to
generate a RMgX species for a telescoped Kumada-Corriu C-C
When screening other variables of the reaction, we learned
that PhBr and PhOTf also successfully participated in the original

2
Tetrahedron
telescoped reaction conditions at ambient temperature. Other
be applied in reaction development. ReactIR has proven to be a
very useful tool to provide greater insight into reaction rate and
mechanism. To this end, we utilized a scale-up of our telescoped
reaction with PhBr to evaluate reaction attributes. In-situ FTIR
was first used to evaluate the hydrogen-metal exchange
(deprotonation) to intermediate 2 and its stability, which was
durable over 14 h. In a second experiment, FTIR was utilized to
understand the C-C coupling en route to product 3. The
combined ReactIR data demonstrated that deprotonation is very
fast (< 15 min) and the coupling is similarly rapid on addition of
a catalyst / PhBr solution (< 20 min, see Fig 1).12 The 20 mmol
(6.2 g) reaction performed as expected, with the quick
deprotonation / coupling delivering product 3 in 79% isolated
yield and >95 A% HPLC purity following silica chromatography.
strong bases could not facilitate the reaction and stoichiometry of
TMPMgCl•LiCl base was important. Varying deprotonation
times indicated that Grignard formation was achieved quickly
and that intermediate reagent stability was on the order of hours.
A preliminary screen of other catalysts demonstrated that only Pd
complexes appeared to work and SPhos8 G2 was most adept at
facilitating the C-C coupling segment of the reaction.9 Solvent
screening uncovered anisole as a more advantageous co-medium
for the PhI coupling.10 Further studies with 1 were conducted
with this anisole protocol.
Table 1. Coupling of pyrazole 1 with diverse ArXa
entry
1
coupling partner
X =
I d
Br
I
Time (h)
%isol. yieldb, c
2
2
1
2
1
2
1
2
1
2
1
2
3
2
1
2
3
2
1
2
1
2
--- (81)
68 (83)
36
2
Br
I
68
3
74
Br
I
64
4
81
Br
I
72
5
60
Br
I
35
6
71
Br
I
72
Figure 1. ReactIR evaluation of coupling of 1 with PhBr
7
53
Br
I
55
Curious to see if the identified ambient temperature conditions
provided a general method for heterocycle functionalization, we
screened several other substrates that had previously been
reported in Knochel-Hauser deprotonation / electrophilic quench
transformations (Table 2).13 1-Methylindazole 4 reacted with PhI
to provide the 3-substituted product in 67% yield (entry 1).14
Isoquinoline 5 returned the desired product in a 53% yield with
the aryl iodide but only a 32% yield with the equivalent bromide
(entries 2 and 3). Meanwhile, 2,6-dichloropyridine 6 generated
the 4-substituted product with PhI but only in 22% yield (entry
4). A further experiment with 30% assay yield proved that
degradation during isolation was not the cause for the low output
(entry 5).
8
40
Br
I
66
9
55
Br
I
36
10
11
59
Br
I
40
56
Br
41
a Metalated species 2a in anisole/THF/toluene treated with 1.2 equiv ArX
and catalyst precursor in anisole at 23 oC. Unless otherwise noted, all
experiments were conducted with 0.651 mmol 1.
Table 2. Coupling of diverse heterocycles with ArXa
entry
1c
coupling partner
ArX
%isol. yieldb
b Isolated following work-up and column chromatography.
4
67
c
Parenthetical values are % HPLC assay yields for 2 h reaction time
points against a standard solution of product of known purity.
d Experiment run at 0.325 mmol scale of 1.
2
5
53
When applied to a variety of ArI and ArBr partners, moderate
to good yields of C-C coupling products were observed in most
cases (Table 1).11 For the parent system, in situ assay yields were
> 80% for both iodo- and bromobenzene with the isolated yield
of the latter at 68% (entry 1). Electron-rich substrates generally
gave higher yields, though variability was noted between the
iodides and bromides in certain cases.
3d
4e
5c, d
6f
32
22
6
--- (30)
58
Process Analytical Technology (PAT) is a powerful approach
to monitor pharmaceutical manufacturing processes but can also

7f
62
2 Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew. Chem., Int. Ed. 2006,
45, 2958-2961.
a
Unless otherwise noted, all experiments were conducted with 0.651
3 Clososki, G. C.; Rohbogner, C. J.; Knochel, P. Angew. Chem., Int. Ed. 2007,
46, 7681. Knochel also reported a direct zincation with TMP2Zn or
TMPZnCl•LiCl to skip the transmetalation prior to the Negishi coupling step.
See: (a) Unsinn, A.; Knochel, P. Chem. Commun. 2012, 48, 2680-2682; (b)
Balkenhohl, M.; Salgues, B.; Hirai, T.; Karaghiosoff, K.; Knochel, P. Org.
Lett. 2018, 20, 3114-3118.
mmol of coupling partner in anisole/THF/toluene, 1.1 equiv TMPMgCl•LiCl,
1.2 equiv ArX, and catalyst precursor in anisole at 23 oC for 1 h, followed by
work-up and isolation after column chromatography.
b
Parenthetical values are % HPLC assay yields for 3 h reaction time
points against a standard solution of product of known purity.
c Experiment run at 0.325 mmol scale of C-H coupling partner.
d Experiment conducted for 3 h.
4 In a resource-constrained world where certain elements – including zinc –
are recognized as “endangered” it is sensible to explore chemistries that can
eliminate stoichiometric applications thereof. See: Sackett, P. Endangered
Elements: Conserving the Building Blocks of Life. Solutions, 2012, 3, 56-62.
5 (a) Tamba, S.; Shono, K.; Sugie, A.; Mori, A. J. Am. Chem. Soc. 2011, 133,
9700-9703; (b) Tanaka, S.; Tamba, S.; Tanaka, D.; Sugie, A.; Mori, A. J. Am.
Chem. Soc. 2011, 133, 16734-16737; (c) Mori, A. J. Synth. Chem. Jpn. 2011,
69, 1202-1211; (d) Tanaka, S.; Tamba,S.; Sugie, A.; Mori, A. Heterocycles,
2012, 86, 255-266; (e) Tamba, S.; Mitsuda, S.; Tanaka, F.; Sugie, A.; Mori,
A. Organometallics 2012, 31, 2263-2267. Additional Zn-free examples make
e Experiment run at 6.62 mmol scale in THF/toluene (no anisole) for 1 h.
f 1.1 equiv TMP2Mg•2LiCl used as base.
The failure of the disubstituted pyridine substrate (6) was
perplexing so we investigated this particular reaction in more
detail. We reexamined solvent composition, other catalysts and
other conditions for this substrate but to no avail. Only when we
looked at a variant of the base, TMP2Mg•2LiCl, did we again see
the desired, higher output of the coupling product with 58%
isolated yield (Table 2, entry 6). Though TMPMgCl•LiCl is a
powerful kinetic base, Knochel et al. reported that
TMP2Mg•2LiCl is a stronger and more selective variant, with
best results from freshly prepared solutions.3 In addition, after
deprotonation ArMgTMP•2LiCl may be stabilized due to
decreased nucleophilicity and greater steric bulk, as reported by
Eaton and coworkers based on their work with the uncomplexed
(no lithium chloride) TMP2Mg base,15 thus allowing for greater
success in transmetalation and C-C bond formation. These
revised conditions with 6 were applied to 2-iodotoluene to give
.
use of BF3 OEt2 to mask an atom while a Knochel-Hauser deprotonation / C-
C coupling is achieved utilizing cryogenic temperatures. See: Klatt, T.;
Roman, D. S.; Leon, T.; Knochel, P. Org. Lett. 2014, 16, 1232-1235.
6 We also looked at Zn(TMP)2, LDA, Mg(DA)2, and i-PrMgCl•LiCl. These
other bases all failed to give metalation that could productively be carried
forward into a C-C coupling. TMP2MgCl•2LiCl also failed for 1 but was later
shown to work with dichloropyridine 6.
7 (a) G. Dahmann, H. Dollinger, C. Gnamm, D. Fiegen, M. Hoffmann, D. J.
Lamb, J. Klicic, A. Schnapp, Preparation of aminoindolyl-substituted
imidazolylpyrimidines as Syk kinase inhibitors for treatment of disease, WO
Patent Application No. 2013/156608; published 24 October, 2013; (b) H.
Chobanian, B. Pio, Y. Guo, F.-X. Ding, S. Dong, S. P. Walsh, J. Jiang, D.
Kim, Preparation of heterocyclic inhibitors of the renal outer medullary
potassium channel for therapy, WO Patent Application No. 2015/095097;
published 25 June, 2015; (c) H.-P. Buchstaller, Preparation of bicyclic
heterocyclic derivatives as pyruvate dehydrogenase kinase (PDHK)
inhibitors, WO Patent Application No. 2017/020981; published 9 February,
2017.
the desired product in 62% yield (entry 7).
While
TMP2Mg•2LiCl is not commercially-available, this base can
easily be prepared from the monomeric TMP magnesium
chloride-lithium chloride complex and offers another option with
challenging substrates in this telescoped transformation.16
8 (a) Martin, R.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3844-3845;
(b) Hua, X.; Masson-Makdissi, J.; Sullivan, R. J.; Newman, S. G. Org. Lett.
2016, 18, 5312-5315.
9 A subsequent HTE screen of palladium catalysts confirmed SPhos G2 to be
preferred mediator, though RuPhos G2 was also shown to accomplish the
transformation.
3. Conclusion
10 Anisole is present as approx. 66% of the total solvent since TMPMgCl•LiCl
is commercially-available as a solution in 1:1 THF/toluene. This aromatic
ether solvent has been shown to benefit arylmagnesium halide basicity,
presumably through stability and solubility factors. See: Westera, G.;
Blomberg, C.; Bickelhaupt, F. J. Organomet. Chem. 1978, 155, C55-C57.
Interestingly, other aryl ethers (EtOPh, CyOPh, t-BuOPh, i-PrOPh, p-
TolOMe) did not facilitate the reaction in the same manner but also showed
poorer overall solubility, indicating that steric accessibility of the ether could
be a critical aspect to anisole’s benefit.
This report describes the direct application of two Knochel-
Hauser bases – TMPMgCl•LiCl and TMP2Mg•2LiCl – to
generate RMgX species for a two-step, telescoped Kumada-
Corriu C-C coupling method with a series of heterocycles and
iodo- or bromobenzene derivatives. The ambient temperature
procedure allows for a mild C-C cross-coupling to a diverse array
of heterocyclic derivatives. The direct application of the initial
RMgX species enables omission of stoichiometric zinc salt.
Further details about the stepwise progression of the
TMPMgCl•2LiCl reaction were monitored with ReactIR to show
that both the deprotonation and C-C coupling are rapid processes.
11 The electrophiles that did not perform well contained pendant functional
groups (CHO, NO2, Ac) which were presumably attacked by the Grignard
intermediate directly without action of the catalyst in the productive C-C
coupling cycle.
12 See SI for more detail.
13 Compounds that failed to participate successfully in our telescoped reaction
included several C-H heterocycles (benzothiazole, benzothiophene, 3-
bromopyridine, 3-bromoquinoline, 3-chloropyridine, ethyl-1-naphthoate,
furan, 1-methylpyrazole, 4-phenylpyridine, thiazole, and thiophene) and X-Ar
derivatives (chlorobenzene, 4-iodoacetophenone, 4-iodobenzaldehyde, and 1-
iodo-4-nitrobenzene). The reasons for these failed reactions could include
one of several steps necessary for the full sequence: (1) inability to achieve
deprotonation, (2) poor transmetalation, or (3) unsuccessful reductive
elimination. These compounds were not investigated further.
14 Substrate 4 reacted cleanly with our reaction conditions. This result stands
in contrast to a recent report indicating that N-substituted indazoles quickly
give the o-aminobenzonitrile via a Kemp-type ring opening elimination. See:
Ganley, J. M.; Yeung, C. S. J. Org. Chem. 2017, 82, 13557−13562.
15 Eaton, P. E.; Lee, C.-H.; Xiong, Y. J. Am. Chem. Soc. 1989, 111, 8016-
8018.
Supplementary Material
Supporting Information associated with this article has been
provided as a separate PDF file.
References and notes
K. C. and S. H. contributed equally to this work. The authors
would like to acknowledge Colin Masui for contributions to
high-throughput experimentation, Harshada Natekar for
conducting high-resolution mass spectrometric analysis, and
Mengling Wong for purification of select compounds.
16 For preparation of TMP2Mg•2LiCl from TMPMgCl•LiCl, see reference 3.
1 Brückl, T.; Baxter, R. D.; Ishihara, Y.; Baran, P. S. Acc. Chem.
Res. 2012, 45, 826-839.

Highlights for A Telescoped Knochel-Hauser / Kumada-Corriu Coupling Strategy to
Functionalized Aromatic Heterocycles:





C-H functionalization via Knochel-Hauser deprotonation under mild conditions
Telescoped Kumada-Corriu cross-coupling to variety of heterocycles
Exclusion of stoichiometric zinc salts (and transmetalation for Negishi coupling)
Benign conditions: room temperature, common solvents, short reaction timeframe
Monitoring reaction progress by ReactIR to demonstrate straightforward methodology

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A Telescoped Knochel-Hauser / Kumada-
Corriu Coupling Strategy to Functionalized
Aromatic Heterocycles
Kyle Clagg, Sara Hold, Archana Kumar, Stefan G. Koenig,* and Remy Angelaud