Hemilabile Benzyl Ether Enables Γ-C(sp3)-H Carbonylation and Olefination of Alcohols

Article abstract of DOI:10.1021/jacs.9b08238

Pd-catalyzed C(sp³)-H activation of alcohol typically shows β-selectivity due to the required distance between the chelating atom in the attached directing group and the targeted C-H bonds. Herein we report the design of a hemilabile directing group which exploits the chelation of a readily removable benzyl ether moiety to direct Γ- or δ-C-H carbonylation and olefination of alcohols. The utility of this approach is also demonstrated in the late-stage C-H functionalization of β-estradiol to rapidly prepare desired analogues that required multi-step syntheses with classical methods.

Full text of DOI:10.1021/jacs.9b08238

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Communication
3
Hemilabile Benzyl Ether Enables #-C(sp)–
H Carbonylation and Olefination of Alcohols
Keita Tanaka, William R. Ewing, and Jin-Quan Yu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b08238 • Publication Date (Web): 13 Sep 2019
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Hemilabile Benzyl Ether Enables -C(sp3)–H Carbonylation and Ole-
fination of Alcohols
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Keita Tanaka,† William R. Ewing,‡ and Jin-Quan Yu*,†
†
Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, United
States
‡ Discovery Chemistry, Bristol-Myers Squibb, PO Box 4000, Princeton, New Jersey 08543, United States
Supporting Information Placeholder
ABSTRACT: Pd-catalyzed C(sp3)–H activation of alcohol typi-
cally shows -selectivity due to the required distance between the
chelating atom in the attached directing group and the targeted C–
elements are crucial for this development: 1) a readily removable
benzyl ether as the directing moiety to control the regioselectivity,
2) a covalently attached ligand to accelerate the C–H activation,
3) the labile ether dissociation to create vacant coordination site to
H bonds. Herein we report the design of hemilabile directing
allow carbonylation and olefination to proceed.
group, which exploit the chelation of a readily removable benzyl
ether moiety to direct , -C–H carbonylation and olefination of
Scheme 1. Strategies for C(sp3)–H activation of alcohols
alcohols. The utility of this approach is also demonstrated in the
late-stage C–H functionalization of β-estradiol to rapidly prepare
desired analogues that required multi-step syntheses with classical
methods.
Alcohol is one of the most abundant structural motifs in the
bioactive natural products and synthetic intermediates. Therefore,
various strategies for the selective C–H functionalization of alco-
hols have been developed. Among them, selective C–H function-
alizations of alcohol derived substrates through intramolecular
nitrene insertion or radical abstraction have been most extensively
investigated and applied to the synthesis of natural products.1 Ir-
catalyzed intramolecular -C(sp3)–H silylation2 (Scheme 1a, eq.
1) and Rh-catalyzed intramolecular δ-C(sp3)–H silylation3 have
also been developed (Scheme 1a, eq. 2). However, development
of hydroxyl-directed C–H metalation and subsequent reaction
with diverse external reagents remains limited to C(sp2)–H
bonds.4,5 The difficulty is largely due to the poor coordination of
the hydroxyl or ether moiety with metal catalysts. To circumvent
this problem, the installation of external chelating groups has been
Since extensive search for ligands and reaction conditions to
employed, which typically afforded -C(sp3)–H arylation of alco-
promote alcohol or ether-directed C(sp3)–H palladation has not
been successful, we decided to covalently attach a previously
hols.6 This regioselectivity is dictated by the distance between the
native functional group (oxygen atom) and targeted C–H bonds
developed APAQ ligand9 to alcohols so that the computed pre-
(Scheme 1bI, left). Although the design of a chelating directing
transition state10 can be assembled intramolecularly. Mindful of
group using ring strain has led to a rare example of reversing - to
practicality of this approach, we employed a broadly used benzyl
ether linkage so that the alcohol products can be furnished by a
standard deprotection (Scheme 2). We also anticipate that the
-selectivity in cyclopalladation7 (Scheme 1bI, right), developing
general strategies for directed -selective C(sp3)–H activation
remains a significant challenge. Furthermore, Pd-catalyzed δ-
Scheme 2. Design of directing group
C(sp3)–H activation of alcohol derived substrates via cyclometal-
lation has not been developed thus far due to the long distance
between the directing group and the -C–H bonds.
Prompted by recent success of using the combination of weakly
coordinating carbonyl groups and a ligand to direct Pd-catalyzed
C(sp3)–H activation,8 we embarked on exploring the hemilabile
coordination of the oxygen atom in alcohols to direct γ- or δ-
C(sp3)–H metalation of alcohols (Scheme 1bII). Herein, we report
the realization of this approach to achieve the first examples of -
and -C(sp3)–H carbonylation and olefination. Three key design
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hemilabile ether must dissociate following the C–H palladation
Table 2. C(sp3)–H carbonylation of alcoholsa,b,c
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step to allow the binding of other reaction partners such as carbon
monoxide and olefin (e.g. Scheme 3A, int-I to int-II).
Substrate 1a was readily prepared by a standard benzylation of
the alcohol substrate with the preformed benzyl chloride bearing
the ligand scaffold (See Supporting Information). Through exten-
sive screening of palladium catalysts, reaction partners and condi-
tions, the carbonylation reaction with CO11,12 was found to be the
most efficient. A number of other directing groups are also evalu-
ated with 1a being optimal (Table 1). The complete loss of reac-
tivity with 1a3 suggest the acceleration from the internal ligand is
crucial (See Supporting Information).
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Table 1. Directing group evaluation for C(sp3)–H carbonyla-
tiona
aThe yield was determined by 1H NMR using 1,3,5-
trimethoxybenzene as the internal standard.
With the optimized reaction conditions in hand13, we examined
the substrate scope (Table 2). Primary-(1a–1g), secondary-(1h–
1p), tertiary-alcohols (1q) all gave moderate to high yields of
products. Substrates containing coordinating oxygen (1e, 1f, and
1n-1p) are also compatible to the reaction conditions. Notably,
these products contain three highly versatile functional groups
with different protecting groups that are amenable for building
complexity. The methylene C–H bonds in the cyclopropane (1r
and 1s) and cyclobutane (1t-1v) substrates are also successfully
converted to ester under the same reaction conditions, affording
highly valuable cyclopropyl and cyclobutyl carboxylic esters. δ-
C(sp3)–H bond activation through remote palladation was also
feasible (2w). Although current conditions gave only moderate
yield (33%), all previous directing groups displayed no reactivity
with δ-C(sp3)–H bond.6,7
b
1
aIsolated yield. The diastereomeric ratio was determined by H
NMR spectroscopy. cAdditive = pentafluorobenzoic acid
Scheme 3A. Proposed catalytic cycle for C(sp3)–H carbonyla-
tion
Based on our preliminary mechanistic studies (see supporting
information) and literatures11,12, we propose a catalytic cycle for
the carbonylation reaction (Scheme 3A). First, the directing group
coordinates to the Pd(II) and triggers the cyclopalladation of C–H
bond accelerated by the NHAc motif participation (Scheme 2),
affording int-I. Then, weak coordinating ether is displaced by
incoming CO to give int-II. Subsequent migratory insertion and
ligand exchange with solvent generate int-III. Finally, reductive
elimination and reoxidation of Pd(0) by Ag(I) close the catalytic
cycle. The essential role of ether coordination was further demon-
strated by the lack of reactivity of substrate 1b1 containing no
ether linkage (Scheme 3B).
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Scheme 3B. Control experiment
30 mg, MeOH 1 mL, H2 1 atm. (See Supporting Information)
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aIsolated yield.
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Guided by the ligand development for C(sp3)–H activation and
computational studies in our laboratory, we have developed
hemilabile benzyl ether directing group to enable γ- and -C(sp3)–
H functionalization of alcohols. Both the acceleration from the
internal ligand and the lability of the ether to dissociate during the
catalytic cycle is essential. The practicality of the benzyl ether
linkage is also an advantageous feature of this reaction. Notably,
Pd-catalyzed C(sp3)–H olefination with ethylene was achieved for
the first time.20 Considering the abundance of hydroxyl containing
natural products and drug molecules, these reactions provide val-
uable means to access bioactive analogues through late-stage
modifications.
Considering the lack of success of C(sp3)–H olefination with the
unactivated olefin,14,15 we applied the same catalytic system to
ethylene insertion reaction, which proceeds through similar mech-
anism to carbonylation reaction (Scheme 4). Since ethylene is the
most abundant two-carbon building block16, this transformation is
potentially useful upon further development.17
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Scheme 4. C(sp3)–H olefination with ethylenea
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
aThe yield was determined by 1H NMR using 1,3,5-
trimethoxybenzene as the internal standard.
Full experimental details and characterization of new
compounds (PDF)
Finally, we demonstrated the potential utility of both the car-
bonylation and olefination with late-stage modification of estro-
gen steroid hormone, β-estradiol (Scheme 5). The substitution at
C13 position was believed to be important for the high bioactivity,
and great number of derivatives at C13 position were prepared by
both pharmaceutical company and academic laboratories.18,19 We
envisioned that these compounds can be synthesized more effi-
ciently by using the new strategy. 1x can be easily prepared from
commercially available β-estradiol by methylation of phenol-
moiety and subsequent auxiliary installation. 1x was subjected to
the carbonylation reaction conditions. Subsequent deprotection
under the hydrogenation conditions gave the cyclized product 4x
in enantiomeric pure form. In contrast, the corresponding race-
mate required 6-step syntheses previously.18 Like-wise, subjecting
1x to the ethylene insertion conditions and subsequent debenzyla-
tion afforded 5x’ which required 17-step syntheses.19
AUTHOR INFORMATION
Corresponding Author
*E-mail: yu200@scripps.edu
ORCID
Jin-Quan Yu: 0000-0003-3560-5774
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We gratefully acknowledge The Scripps Research Institute and
NIH (NIGMS, 2R01 GM084019) for financial support. We thank
Dr. Jason Chen, Ms. Brittany Sanchez and Ms. Emily Sturgell
from Automated Synthesis Facility, The Scripps Research Insti-
tute for their assistance with HRMS analysis.
Scheme 5. Late-stage derivatization of β-estradiola
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