Rhodium(III)-Catalyzed C-H Activation: Ligand-Controlled Regioselective Synthesis of 4-Methyl-Substituted Dihydroisoquinolones

Article abstract of DOI:10.1021/acs.orglett.9b02029

Rh-catalyzed C-H functionalization of O-pivaloyl benzhydroxamic acids with propene gas provides access to 4-methyl-substituted dihydroisoquinolones. Good to excellent levels of regioselectivity are achieved using [Cp^tRhCl₂]₂ as a precatalyst under optimized conditions. Thorough examination of aryl/heteroaryl O-pivaloyl hydroxamic acid substrates, ligand effects on C-H site selectivity, alkene scope, and demonstration of scale are discussed within.

Full text of DOI:10.1021/acs.orglett.9b02029

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Rhodium(III)-Catalyzed C−H Activation: Ligand-Controlled
Regioselective Synthesis of 4‑Methyl-Substituted
Dihydroisoquinolones
†
́
Joyann S. Barber, Stephanie Scales, Michelle Tran-Dube, Fen Wang, Neal W. Sach, Louise Bernier,
Michael R. Collins, JinJiang Zhu, Indrawan J. McAlpine, and Ryan L. Patman*
Pfizer Oncology Medicinal Chemistry, 10770 Science Center Drive, San Diego, California 92121, United States
S
* Supporting Information
ABSTRACT: Rh-catalyzed C−H functionalization of O-pivaloyl benzhydroxamic acids with propene gas provides access to 4-
methyl-substituted dihydroisoquinolones. Good to excellent levels of regioselectivity are achieved using [CptRhCl2]2 as a
precatalyst under optimized conditions. Thorough examination of aryl/heteroaryl O-pivaloyl hydroxamic acid substrates, ligand
effects on C−H site selectivity, alkene scope, and demonstration of scale are discussed within.
etrahydroisoquinolines (THIQs) and their dihydroisoqui-
our projects at Pfizer, our objective in the present study was to
enable a direct regioselective method for their synthesis.
Transition-metal-catalyzed C−H alkylation reactions utilizing
alkenes represent a powerful class of C−C bond-forming
transformations within organic chemistry.8 Over the past
decade, Rh(III)-catalyzed C−H functionalization, in particular,
has emerged as an effective approach for the synthesis of small
molecules due to the functional group tolerance and mild
reaction conditions often employed.9 In 2011, Fagnou10a and
Glorius10b independently reported the first annulations of O-
pivaloyl benzhydroxamic acids with π-unsaturates (Scheme 1a).
Following these seminal reports, significant progress has been
made toward rendering alkene insertions of this type regio-11
and stereoselective.12 Of these studies, we were particularly
inspired by the work of Rovis et al.,11b,d wherein they describe a
ligand-directed strategy for the regioselective insertion of alkyl-
substituted alkenes, giving rise to 4-substituted dihydroisoqui-
nolones (Scheme 1b). Though annulations of gaseous olefins
were not described in their study and remain largely unexplored
in this context, our laboratory was intrigued by the possibility of
employing propene as an atom-economical C3 carbon source to
synthesize pharmaceutically relevant 4-methyl-substituted dihy-
droisoquinolones. Therefore, we focused this investigation on
evaluating the regioselectivity and optimal conditions for
propene delivery using rhodium-based catalysts in this trans-
formation.
T
nolone analogues are privileged scaffolds found within
naturally occurring alkaloids1 and numerous drug discovery
programs2 (Figure 1). For example, Palonosetron is a 5-HT3
Figure 1. Representative examples of bioactive molecules bearing the 4-
substituted isoquinoline motif.3−5
antagonist approved for the treatment of chemotherapy-induced
nausea and vomiting.3 Gliquidone, a prescribed antidiabetes
treatment, also bears this structural motif.4 Further survey of the
literature reveals that 4-methyl-substituted derivatives are
commonly prepared during lead optimization campaigns.5
Strategic incorporation of small substituents in drug design
(e.g., the colloquial “magic methyl”)6 has the potential to
dramatically improve the bioactivity, pharmacokinetics, and off-
target selectivity for a given lead or series while increasing
lipophilic efficiency.7 Motivated by the need for efficient access
to diverse 4-methyl-substituted dihydroisoquinolones on one of
We began by benchmarking our optimization efforts with
reaction conditions previously reported in the literature10a,11d to
test the feasibility of our desired annulation reaction with O-
Received: June 12, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02029
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
propene) and high dilution (0.01 M TFE) used in our high-
throughput screening platform should be modified for
transitioning these conditions to laboratory scale. Harnessing
the optimized components of CsOPiv and TFE, we turned our
attention to evaluating the effect of temperature and reaction
duration at a more conventional reaction concentration (0.2 M
TFE). Additionally, we utilized a balloon filled with propene as
our preferred method for gas delivery. At room temperature, we
observed catalyst turnover to be sluggish with a significant
amount of starting material left unreacted. Despite this fact, we
obtained a promising 7-fold improvement in isolated yield after
the reaction was stirred for 48 h under an atmosphere of propene
(entry 4). By moderately increasing the temperature to 40 °C,
we achieved full conversion of starting material after 18 h,
furnishing a 68% yield of 3a after flash column chromatography
(entry 5). Last, we note that our procedure for setting up the
reaction is relatively straightforward and does not require
rigorous exclusion of oxygen or moisture.
Scheme 1. Rh(III)-Catalyzed Annulation of O-Pivaloyl
Hydroxamic Acids with Alkenes via C−H Activation10,11b
With the reaction conditions optimized to our satisfaction, we
sought to examine the scope and limitations of this reaction
(Scheme 2). A diverse set of O-pivaloyl benzhydroxamic acids 1
were prepared and examined under these conditions en route to
4-methyl-substituted dihydroisoquinolones 3. The simplest
expression of these involved synthesis of 3b, which was achieved
in 76% yield and 17:1 regioisomeric ratio (rr). Electron-
withdrawing (examples 3c and 3e) as well as electron-donating
(example 3d) substituents were tolerated para to the
hydroxamate. Substitution ortho to the site of C−H insertion
was also tolerated, exemplified by example 3f, albeit with a small
loss of regiocontrol typically observed. As illustrated with our
model substrate 1a, ortho-substitution of the hydroxamate with
benzyloxy, fluoro, and methyl groups delivered synthetically
useful amounts of our desired products 3g−i. In these cases,
however, we believe electrostatic repulsion and steric hindrance
can both play a role in disrupting the concerted metalation−
deprotonation event by increasing the dihedral angle between
the hydroxamate−metal complex and arene C−H bond.14
Ultimately, we observed diminished conversions as these effects
became more pronounced. To further highlight this observation,
we prepared 2-chloro-N-(pivaloyloxy)benzamide 1j and sub-
mitted it to the reaction conditions, wherein we found that only
a trace of product 3j could be detected. Heterocyclic substrates
containing furan or thiophene motifs performed exceptionally
well under these conditions to furnish products 3k−3m in
excellent yield and regioselectivity. Nitrogen-containing hetero-
cycles, however, proved to be more challenging with pyrazole 1n
pivaloyl hydroxamic acid 1a and propene gas 2a (Table 1).
Under identical conditions, using cesium acetate (CsOAc) as
the base and methanol as the reaction solvent, the reactivity and
regioselectivity of [Cp*RhCl2]2 and [CptRhCl2]2 catalysts were
compared at room temperature (entries 1 and 2). We found that
[Cp*RhCl2]2 gave slightly higher yield (11%); however, no
appreciable regioselectivity for the formation of 3a was achieved
(entry 1). On the other hand, by employing the [CptRhCl2]2
catalyst utilized by Rovis and co-workers,11b,d the dihydroiso-
quinolone product 3a could be accessed in ⩾20:1 regioselec-
tivity (entry 2). At this stage, we performed NMR analysis of the
isolated product (entry 2), and through 2D 19F−1H hetero-
nuclear (NOE) correlation spectroscopy, we were able to
confirm the structure as the 4-methyl-substituted regioisomer
3a. Excited by the excellent regioselectivity obtained for our
model substrate, we proceeded with a high-throughput
optimization study to identify the ideal base and solvent to be
used with [CptRhCl2]2 for the insertion of propene 2a (entry 3).
Several of the weak bases we examined displayed promising
conversions with cesium pivalate (CsOPiv), performing slightly
better than the others. Most notably, however, we observed that
2,2,2-trifluoroethanol (TFE) was unique in its capacity to
deliver the desired product 3a in high conversion.13 From a
practical perspective, we felt the increased pressure (2 atm
a
Table 1. Selected Optimization Experiments for Rh(III)-Catalyzed Annulations with Propene Gas
entry
catalyst
loading (mol %)
base
solvent
temp (°C)
time (h)
yield (%)
rr
1
2
3
4
5
[Cp*RhCl2]2
1.0
1.0
CsOAc
CsOAc
MeOH (0.1 M)
MeOH (0.1 M)
high-throughput optimization
TFE (0.2 M)
23
23
18
18
11
5
1.3:1
>20:1
[CptRhCl2]2
b
[CptRhCl2]2
[CptRhCl2]2
2.5
2.5
CsOPiv
CsOPiv
23
40
48
18
38
68
15:1
11:1
TFE (0.2 M)
a
Regioisomeric ratios (rr) were determined by 1H NMR analysis of the crude reaction mixtures, and percent yields correspond to isolated products.
See Supporting Information for details.
b
B
DOI: 10.1021/acs.orglett.9b02029
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Organic Letters
Letter
a b
,
a b
,
Scheme 2. O-Pivaloylhydroxamic Acid Scope
Scheme 3. Examination of C−H Site Selectivity
a
All reactions were run on a 0.3 mmol scale unless otherwise noted.
Regioisomeric ratios (rr) were determined by H NMR analysis of
b
1
the crude reaction mixtures, and percent yields correspond to isolated
products.
a
All reactions were run on a 0.3 mmol scale unless otherwise noted.
b
1
Regioisomeric ratios (rr) were determined by H NMR analysis of
reaction partner, enabling access to naphthyridinone 3v through
preferential activation at the 2-position.
the crude reaction mixtures, and percent yields correspond to isolated
products.
Having surveyed the scope of O-pivaloyl benzhydroxamic
acids, we briefly evaluated additional olefinic substrates under
our optimized conditions (Scheme 4). Here, we found that
alkyl-substituted terminal alkenes delivered the 4-substituted
dihydroisoquinolones 3w−3y in yields and regioselectivities
comparable to those described by Rovis11b,d and have
unambiguously assigned the structure of 3w through X-ray
providing a modest 16% isolated yield of the desired
tetrahydropyrazolopyridinone 3n. Nicotinic acid derivative 1o
and its N-oxide analogue 1p, known to be successful substrates
in previous studies employing the prototypical [Cp*RhCl2]2
catalyst,11h were not successful under these conditions.
To further explore the scope of this transformation, we
prepared several additional substrates possessing two potential
sites for C−H activation (Scheme 3). In general, we found the
Handy method useful as starting point for predicting C−H site
selectivity a priori (e.g., 3k, Scheme 2).15 However, when bulky
substituents are introduced proximally to one of the potential
sites for activation, this analysis can fail. For example, substrates
bearing meta-acetyl 1q or meta-trifluoromethyl 1r groups were
found to react preferentially at the least sterically encumbered
position, overriding the innate preference for activation of the
most deshielded C−H bond, thus delivering propene adducts
3q−3r in excellent yield, regioselectivity, and C−H site
selectivity. Reducing the molecular volume of the group ortho
to the most acidic C−H bond restores selectivity for that
position as the predominant site for activation, as demonstrated
by examples 3s−3t. Of particular significance to medicinal
chemists, we demonstrated that pyrrolopyridinone 3u could be
accessed efficiently in good regio-/site selectivity. Additionally,
though nicotinates 1o and 1p were ineffectual, we were pleased
to find that CF3-substituted nicotinate 1v was a competent
a b
,
Scheme 4. Olefin Substrate Scope
a
All reactions were run on a 0.3 mmol scale unless otherwise noted.
Regioisomeric ratios (rr) were determined by H NMR analysis of
b
1
the crude reaction mixtures, and percent yields correspond to isolated
products.
C
DOI: 10.1021/acs.orglett.9b02029
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Organic Letters
Letter
crystallography (CCDC 1916101). Additionally, we found that
the ligand-mediated regiocontrol provided by the [CptRhCl2]2
catalyst could not overcome the electronic bias of styrene, thus
the 3-substituted congener 3z was obtained in this instance.
Styrenes are known to display this inherent regiochemical
preference.10
To conclude our study, we sought to establish that our
optimized procedure could be performed successfully on >1 g of
substrate, a 10-fold increase from our standard conditions, with
the objective of facilitating multistep syntheses (Scheme 5). For
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ryan.patman@pfizer.com.
ORCID
Ryan L. Patman: 0000-0003-2363-8368
Present Address
†J.S.B.: Department of Chemistry and Biochemistry, University
of California, Los Angeles, CA 90095.
Notes
a
Scheme 5. Gram-Scale Synthesis
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
J.S.B. gratefully acknowledges the Pfizer Summer Student
Worker Program for an internship. We would like to thank
Dr. Alex Yanovsky (Pfizer), Dr. Milan Gembicky (UCSD), and
Dr. Arnold L. Rheingold (UCSD) for X-ray structure support,
Dr. Wei Wang (Pfizer) and Jason Ewanicki (Pfizer) for NMR
support, and Jeff Elleraas (Pfizer) and Phuong Tran (Pfizer) for
purification support. We further thank Dr. Jennifer Lafontaine
(Pfizer), Dr. Sajiv Nair (Pfizer), and Dr. Patrick Montgomery
(Pfizer) for helpful discussion and review of this manuscript.
a
1
Regioisomeric ratios (rr) were determined by H NMR analysis of
the crude reaction mixtures, and percent yields correspond to isolated
products.
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on a smaller scale. Moreover, dihydroisoquinolone 3a could be
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In summary, we have developed a convenient method for
annulation of O-pivaloyl benzhydroxamic acids with propene
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useful platform for adaptation to larger-scale applications later in
the drug development process.
■
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