Synthesis of Lactones via C-H Functionalization of Nonactivated C(sp3)-H Bonds

Article abstract of DOI:10.1021/acs.orglett.6b03371

An electron-deficient amide is utilized as a directing group to functionalize nonactivated C(sp³)-H bonds through radical 1,5-hydrogen abstraction. The γ-bromoamides formed are subsequently converted to γ-lactones under mild conditions. The method described is not limited to tertiary and secondary positions but also allows functionalization of primary nonactivated sp³-hybridized positions in a one-pot sequence. In addition, the broad functional group tolerance renders this method suitable for the late-stage introduction of γ-lactones into complex carbon frameworks.

Full text of DOI:10.1021/acs.orglett.6b03371

Letter
pubs.acs.org/OrgLett
Synthesis of Lactones via C−H Functionalization of Nonactivated
C(sp3)−H Bonds
Johannes Richers,†,∥ Michael Heilmann,‡,∥ Markus Drees,† and Konrad Tiefenbacher*,‡,§
†Department of Chemistry, Technical University of Munich, Lichtenbergstraße 4, 85747 Garching, Germany
‡Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland
§Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland
S
* Supporting Information
ABSTRACT: An electron-deficient amide is utilized as a
directing group to functionalize nonactivated C(sp3)−H bonds
through radical 1,5-hydrogen abstraction. The γ-bromoamides
formed are subsequently converted to γ-lactones under mild
conditions. The method described is not limited to tertiary and
secondary positions but also allows functionalization of
primary nonactivated sp3-hybridized positions in a one-pot
sequence. In addition, the broad functional group tolerance
renders this method suitable for the late-stage introduction of
γ-lactones into complex carbon frameworks.
actone rings occur as a common and widespread structural
Lmotif in natural and synthetic compounds. In particular,
many fine chemicals, natural products, and pharmaceuticals
comprise saturated γ-lactones. Naturally occurring lactones, such
as γ-decalactone (1), often contribute to the aromas of various
foods and fruits or exhibit interesting biological activities such as
the neurotrophic sesquiterpene jiadifenolide (2) or the
antibacterial peptidoglycan biosynthesis inhibitor avenaciolide
(3) (Figure 1a).1 Most methods for synthesizing saturated γ-
lactones, such as halolactonization or intramolecular substitu-
tions, depend on prefunctionalized γ-positions with either
electrophilic or nucleophilic properties (Figure 1b).2 In nature,
however, in many cases such oxygen heterocycles are introduced
by selective oxidation of scarcely functionalized carbon frame-
works by powerful oxidases such as the heme and non-heme iron
enzyme families.3
Since the pioneering observations of Hofmann, Loffler, and
̈
Freytag,4 a variety of methods have been established to transform
C−H bonds directly. New concepts enabling innate and directed
C−H functionalizations with control over regio- and stereo-
selectivity are emerging, including transition-metal-catalyzed
reactions.5 Nevertheless, the extraordinary properties of nitro-
gen-centered radicals and the high selectivity of radical hydrogen
abstractions still inspire scientists to develop novel methods for
controlled oxidation in a variety of applications.6 Since the 1960s,
there have been reports that amidyl radicals can in principle be
used to form γ-lactones via hydrogen abstraction.7 Nevertheless,
such a lactonization has not found application in synthesis. As
Figure 1. (a) Selection of natural products containing γ-lactones. (b)
Retrosynthetic approaches toward γ-lactones. (c) Mechanistic descrip-
tion of lactone formation.
would operate under mild conditions and tolerate a wide variety
of functional groups. To find solutions for this challenge, we
conducted a systematic investigation of the radical-mediated
Suar
́
ez stated in 2005,8 this is due to the narrow scope, low
chemical yields, and poor reproducibility of the procedures
published. A method that allows the functionalization of
nonactivated tertiary, secondary, and also primary C−H bonds
is highly desirable but has not been available to date. Ideally, it
Received: November 11, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03371
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Letter
synthesis of lactones utilizing amidyl-directed C−H functional-
ization. This strategy would follow the mechanism depicted in
Figure 1c. Here carboxylic acid 4 is converted to the amide,
followed by N-bromination to afford the labile N-bromo species
6. Upon irradiation, this compound forms a nitrogen-centered
radical, which can undergo 1,5-H abstraction via the six-
membered transition state T1. Radical recombination gives rise
to γ-bromoamide 7, which then should allow cyclization to form
iminium lactone 8 over the amide.9 Hydrolysis then yields lactone
5.
conditions, such as refluxing sulfuric acid.7c,13 In contrast, we
were able to isolate the lactones under very mild conditions. This
underscores the advantageous properties of the trifluoroethyl
amide as a directing group, as it displays an optimal balance of
electron deficiency, O-nucleophilicity, and hydrolyzability.
Next, we looked at a series of simple substrates to evaluate
whether different aliphatic sp3 positions could be functionalized.
Starting from commercially available carboxylic acids, a series of
γ-lactones were synthesized by conversion of the respective
amides inaone-pot lactonization protocol (Table 2;for screening
First, different substituents were screened for their aptitude to
achieve the desired C−H functionalization on the test substrate
pentanoic amide (Table 1). Acetyl hypobromite and white light-
Table 2. Synthesis of Tertiary, Secondary, and Primary γ-
Lactones
a
Table 1. Screening of N Substituents
a
b
R = CH2CF3. Determined using CH2Br2 as an internal standard.
a
c
Complex product mixture; no γ-bromination was observed.
Cyclization product.
Isolated yield.
b
details, see Table S1). Notably, not only tertiary (21, 22, and 23)
and secondary (24, 25, and 26), but also primary C(sp3)−H
bonds (27, 28, and 29) were found to be readily functionalized
this way, giving rise to the respective γ-lactones in good to
excellent yields. Besides compounds with various alkyl lengths,
also spirocyclic structures (23) as well as α-substituted lactones
(25, 27, and 28) are accessible.
To investigate the scope and the limitations of the reaction, a
series of more complex structures were synthesized and
converted to the respective lactones. Here the fully optimized
protocol was utilized (Table S1). As depicted in Table 3, the
lactone moiety could be introduced into a variety of structures
with different functional groups such as ketones (30), protected
amines (31), aryl units (32), and electron-deficient olefins (33).
Complex polycyclic γ-lactones (34, 35) and bislactones (36)
were also synthesized. In several cases (32b, 33b, 35b, 36b, and
37b), the yield was improved by utilizing AgOAc instead of
AgBF4 to promote cyclization.
As with most C−H oxidation methods, electron-rich alkenes
and enones do not tolerate the radical reaction step; in the case of
an epoxide-containing substrate we investigated, γ-bromination
was successful, but the cyclization conditions required were not
compatible (see Table S2). Moreover, a limitation was found in
the case of sterically hindered substrates: α-quaternary amides
failed to undergo N-halogenation, while one substrate with a
sterically very demanding γ-substituent failed to undergo H-
abstraction. DFT calculations indicated that in this case the
transition state energy was considerably higher than in the case of
regular substrates (further discussion and mechanistic details
emitting diodes (LEDs) were used to generate the N-bromo
species and initiate the radical reaction, respectively. It became
evident that many substituents show either no γ-bromination (9,
10, 13, and 20) or moderate ratios of product to starting material
(11, 12, 14, and 19). Very good results were obtained with tert-
butyl amide 16 (93:7; Table 1). However, the tert-butyl amide
underwent spontaneous cyclization to form the iminium lactone,
which proved to be unreactive under a variety of hydrolysis
methods, presumably because of the steric bulk of the tert-butyl
group. Calculations and experiments have indicated that
especially electron-deficient amidyl radicals tend to undergo
hydrogen abstractions readily.6a,10 Since the trifluoroethyl group
has proven to be suitable for the carbamate-directed synthesis of
1,3-diols as demonstrated by the Baran group,6b we investigated
the reaction with trifluoroethyl-substituted amide 17. We were
pleased to observe that in this case the hydrogen abstraction led
to the formation of the C−H functionalized product in an
excellent ratio (90:10) without formation of any side products.
With a simple route to the γ-bromoamide established, we turned
our attention to different cyclization methods and found that
formation of the iminium lactone could be easily induced with the
addition of silver(I) tetrafluoroborate under mild conditions.11
However, attempts to isolate and purify the iminolactone after
deprotonation with base were unsuccessful.12 Instead, facile
hydrolysis was achieved at room temperature by direct addition
of water to the reaction mixture. This finding was unexpected in
that tert-butyl iminolactones (8, R = tert-butyl; Figure 1) formed
from tert-butyl amides could be hydrolyzed only under harsh
B
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a
In conclusion, the first general method has been developed that
allows the introduction of lactone rings by amide-directed C−H
functionalization in good to excellent yields with unprecedented
scope. Although nitrogen radical chemistry has been known since
the age-old HLF reaction, this work features two major advances
by employing the trifluoroethyl amide as a directing group: (1)
the highly efficient hydrogen abstraction, which is not limited to
tertiary and secondary sp3 positions but is also suitable for the
conversion of primary nonactivated methyl groups, and (2) the
efficient cyclization and mild hydrolysis, which allow the direct
and simple synthesis of γ-lactones in a one-pot fashion in the
presence of a variety of functional groups. In total, 19 different
substrates were converted successfully, showcasing highly
predictable selectivity, good functional group tolerance, and
broad scope for the functionalization of aliphatic C−H bonds.
Since lactones are prominent structural features of many
synthetic compounds and natural products, application of this
C−H lactonization method will open up novel routes, including
biomimetic late-stage C−H oxidations.
Table 3. Scope and Limitations
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b03371.
Experimental procedures and spectral data for all new
compounds and DFT calculations (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: konrad.tiefenbacher@unibas.ch, tkonrad@ethz.ch.
ORCID
Konrad Tiefenbacher: 0000-0002-3351-6121
Author Contributions
∥J.R. and M.H. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
a
b
R = CH2CF3; TCP = tetrachlorophthalimide. Isolated yield.
AgOAc then AcOH, H2O instead of AgBF4 then H2O for (2).
This work was funded by the Deutsche Forschungsgemeinschaft.
The support of Prof. Thorsten Bach and his group (TUM) is
acknowledged.
c
d
e
Determined using CH2Br2 as an internal standard. No further
defined product was isolated.
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