Photo-induced formation of cyclopropanols from α-ketoamides via γ-C-H bond activation

Article abstract of DOI:10.1016/j.tetlet.2015.09.038

A novel type of photocyclization of α-ketoamides was developed, affording unique cyclopropanols bearing amide functionality. N-tert-Butyl, N-trityl, or N-non-substituted α-ketoamides with a bulky substituent at the β-position of the amide functionality were efficiently converted to corresponding cyclopropanols through the activation of the γ-C-H bond followed by C-C bond formation between the α- and γ-positions of the amide. Hydrogen abstraction from the γ-position of the amide was considered to be the rate-determining step of cyclopropanol formation, based on the kinetic isotope effect. Cyclopropanols could be converted to two different types of functionalized α-ketoamides depending on the method of ring-opening.

Full text of DOI:10.1016/j.tetlet.2015.09.038

Tetrahedron Letters 56 (2015) 5991–5994
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Photo-induced formation of cyclopropanols from
-CAH bond activation
a-ketoamides via
c
d
b
Eisuke Ota a,b, Yu Mikame a,c, Go Hirai a,d,e, , Hiroyuki Koshino , Shigeru Nishiyama ,
⇑
Mikiko Sodeoka a,d,e,
⇑
a RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
b Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan
c Department of Life Science and Biotechnology, Tokyo University of Agriculture and Technology, 2-24-16, Naka-cho, Koganei, Tokyo 184-8588, Japan
d RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
e AMED-CREST, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel type of photocyclization of
bearing amide functionality. N-tert-Butyl, N-trityl, or N-non-substituted
a
-ketoamides was developed, affording unique cyclopropanols
-ketoamides with a bulky
substituent at the b-position of the amide functionality were efficiently converted to corresponding
cyclopropanols through the activation of the -CAH bond followed by CAC bond formation between
the - and -positions of the amide. Hydrogen abstraction from the -position of the amide was
considered to be the rate-determining step of cyclopropanol formation, based on the kinetic isotope
Received 31 August 2015
Revised 8 September 2015
Accepted 13 September 2015
Available online 15 September 2015
a
c
a
c
c
Keywords:
Photo chemical reaction
Cyclopropanols
effect. Cyclopropanols could be converted to two different types of functionalized
depending on the method of ring-opening.
a-ketoamides
Ó 2015 Elsevier Ltd. All rights reserved.
Kinetic isotope effect
a-Ketoamides
Ring-opening reactions
The photochemistry of
a
-dicarbonyls has been extensively
-ketoamides 1
affords 1,4-biradical species
According to Whitten’s report, b-lactam derivatives 2
5
after electron reorganization.
are
investigated.1 In particular, the photoreaction of
a
to produce b-lactam derivatives 2 and/or oxazolidinone derivatives
3 as the main products (so-called Norrish type-II reaction) is well-
known (Scheme 1-1)2 in organic synthesis, because it enables
direct CAC (Norrish–Yang cyclization to form 2) or CAO bond
formation (to form 3) through selective cleavage of the CAH bond3
constructed via the intramolecular radical coupling reaction. In
contrast, electron transfer can occur again to form another zwitte-
rion species 6 as a precursor of the oxazolidinone derivatives 3.
In many cases, N,N-disubstituted
to afford better results as substrates, since the keto-functionality
and -position of the N-atom are placed close to each other. Sev-
a-ketoamides 1 are expected
at the
a-position of the N-atom (N
a-proton). Moreover, the
a
a
-dicarbonyl system is conveniently activated by irradiation at
eral examples of photolysis of N-monosubstituted a-ketoamides
relatively long wavelength compared to other standard functional
groups in organic molecules. Various applications to the synthesis
of biologically active molecules4 or asymmetric reactions in chiral
crystals5 have also been reported.6
have been reported.9 On the other hand, photo-induced
cyclopropanol formation of ketones10 has been reported only for
a limited range of substrates, such as b-amino-,11 b-oxy-,13 or
a
-methylene-ketones,12 in which the 1,4-hydrogen shift would
Based on the intensive experiments by Aoyama’s group7 and
Whitten’s group,8 the mechanism of formation of 2 and 3 was pro-
posed to be as follows (Scheme 1-1). Irradiation of 1 induces n–p⁄
transition and generates the singlet excited state. The amide func-
tionality serves to quench the excitation state via an electron
transfer process to generate the transient zwitterion species 4.
be facilitated due to stabilization of the radical at the b-position
by a heteroatom or double bond. However, as far as we know,
no example of photo-induced cyclopropanol formation of
a
-ketoamides has been reported. We hypothesized that the forma-
tion of cyclopropanol 8 would be possible for N-monosubstituted
-ketoamides 7, which favor s-trans conformation (Scheme 1-2).
In contrast to the simple ketone, -ketoamides 7 are expected
a
Since the acidity of the N
a
-proton would be increased, abstraction
a
of the H-atom followed by protonation of the carbonyl O-atom
to be activated by irradiation at a longer wavelength (longer
than 300 nm) and to generate the transient zwitterion species 9.
We speculated that the amide functionality in 9 would facili-
⇑
Corresponding authors. Fax: +81 48 462 4666.
E-mail addresses: gohirai@riken.jp (G. Hirai), sodeoka@riken.jp (M. Sodeoka).
tate abstraction of the unactivated
c-CAH bond to generate
http://dx.doi.org/10.1016/j.tetlet.2015.09.038
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

5992
E. Ota et al. / Tetrahedron Letters 56 (2015) 5991–5994
Table 1
Effect of substituent on N-atom
Entry
Substrate
R
Time (h)
Product: yield (%)
1
2
3
4
5
6
7d
8
14a
14b
14c
14d
14e
14f
14f
14g
CH2Ph
COPh
CO(CH2)4CH3
OtBu
1.5
11
1
12
3
12
11
5 min
15a: 13a
15b: 28
15c: 31
15d: 0b
15e: 71
15f: 50c
15f: 99
15g: 94
tBu
CPh3
CPh3
H
a
b
c
14b (31%) and 15b (24%) were obtained.
Starting material was recovered (98%).
Starting material was recovered (49%).
Reaction solvent: 2-BuOH.
d
was still predominant (entries 2 and 3). Although no photo-
reaction of t-butyl hydroxamate 14d occurred at all, to our
delight, we found that the irradiation of t-butyl amide 14e
afforded the corresponding cyclopropanol 15e in 71% yield (entries
4 and 5). In addition, the photo-reaction of the trityl-protected
amide 14f proceeded cleanly (entry 6), though with only moderate
conversion. Since transient formation of the hemiacetal with
methanol may disturb the reaction,18 solvent screening was
performed (see Table S1).17 We found that the use of 2-butanol
was effective, providing 14f in almost quantitative yields (entry
7). Furthermore, it was found that the photo-reaction of the
simple (N-non-substituted) 3,3-dimethyl-2-oxobutyramide (14g)
was completed within 5 min, and 1-hydroxy-2,2-dimethylcyclo-
propanecarboxamide (15g) was obtained in 94% yield (entry 8).
With this knowledge of the effects of N-atom substituents and
solvent in hand, we next investigated variations of the ketone.
For easy monitoring of the proto-reaction by TLC, UV-active tri-
tyl-protected amides 16 were selected (Scheme 2). Preparation of
16 is shown in Schemes S3–S5.17 Photo-reaction of 16a–16c
bearing a substituent Y (Me, OBn, or OTBS) proceeded smoothly
to provide the corresponding cyclopropanols syn-17a–17c and
their diastereomers anti-17a–17c in excellent yields. The stereo-
chemistry of these products was mainly determined from their
HMBC spectra. Namely, a stronger HMBC correlation from Ha to
the C-atom of the amide carbonyl group was observed in the
major isomers. We considered that this would be attributed to
the syn-orientation (dihedral angle = ꢀ0°) of these atoms, which
should show a larger coupling constant (J value) than the corre-
sponding anti-isomers (dihedral angle = ꢀ135°). This consideration
was supported by DFT calculations as well as by the different
intensities of the HMBC correlations observed between Ha and
the two methyl groups on cyclopropanols (Figs. S2–S6).17
Scheme 1. (1) Photo-reaction of
formation of cyclopropanol derivatives.
a-ketoamides; (2) working hypothesis for the
1,3-biradical species 11, which is then converted to the cyclo-
propanol product. Namely, the rapid proton transfer from the
N-atom to the oxygen atom (from 9 to 10, instead of transfer of
the N
the -position to the amide owing to its radical character (from
10 to 11) result in
-CAH bond activation.14 The highly substituted
a-proton in the case of 1) and the 1,5-hydrogen shift from
c
c
cyclopropanol 8 bearing amide functionality is expected to be a
unique synthetic building block for organic synthesis. Since
various types of ring-opening reactions of cyclopropanol15 are
known, 8 could be converted to the
amides 12 or 13. The overall transformation is regarded as func-
c-position-functionalized
tionalization of the
the framework.
c-position, with or without rearrangement of
To test our working hypothesis, 3,3-dimethyl-2-oxobutyra-
mides 14 having a substituent on the N-atom were selected as
substrates for initial examination. Normally, functionalization of
the CAH bond on the t-butyl group is challenging without a special
directing group,16 but we expected that 3 equivalent methyl
groups at the
c-position would facilitate the desired reaction
(Table 1). All reactions were conducted in glass tubes under a blue
LED lamp (max. output 365 nm) under degassed conditions
It should be noted that no cyclized product at the methyl group
18a–18c was detected in the photochemical reaction of 16a–16c.
In contrast, the reaction of 16d with an acetoxy group provided
regio-isomer 18d as a major product (80%) along with a small
amount of syn-17d (4%). The stereochemistry of these molecules
was assigned in the same manner as described above (see also
Figs. S7–S8).17 These results indicated that the selective formation
of cyclopropanols 17 and 18 can be achieved by the choice of a
suitable substituent on the O-atom. On the other hand, photolysis
of non-protected 16e did not produce any cyclopropanol deriva-
tive. Instead, disproportionation occurred to give 19 in moderate
yields.19 In addition, 16f with a bromine atom was converted to
(see Fig. S1).17 Preparation of
a-ketoamides 14 is summarized in
Schemes S1 and S2.17 As we expected, photolysis of benzyl amide
14a gave the isolable cyclopropanol 15a, though in low yields
(entry 1). Neither b-lactam 2 nor oxazolidinone 3 was detected.
Instead, imide 14b or its cyclized product 15b was isolated.
This observation suggested that H-atom abstraction from the
Na
-proton competes with the desired reaction pathway. Hence,
imide-type 14b (phenyl) and 14c (n-pentyl) without N -protons
a
were investigated as substrates. As a result, cyclopropanol forma-
tion was slightly improved, but degradation of the substrates

E. Ota et al. / Tetrahedron Letters 56 (2015) 5991–5994
5993
Scheme 3. Photolysis of the mixture of 14f and 14f-d9.
Scheme 4. Allylation and bromination of cyclopropanol 15f.
Scheme 2. Photo-induced cyclopropanol formations of a-ketoamides 15.
of ring-opening. After several investigations, we found that the
treatment of 15f with Ce(NH4)2(NO3)6 (CAN) and KBr21 resulted
in the introduction of bromine at the less-hindered site of cyclo-
propanol to produce 16f in moderate yields. These results suggest
b,c-unsaturated a-ketoamide 20 through cyclopropanol formation
followed by simultaneous b-elimination and ring-opening.
This reaction was applicable to substrates with bulkier
substituents, and photolysis of 16g and 16h afforded the unique
cyclopropanols 17g, 17h, and 18h. In all cases, H-atoms on the
more-substituted carbon center were selectively abstracted, as in
the reactions of 16a–16c. On the other hand, photo-reaction of
that a variety of
a-ketoamide derivatives could be prepared from
the photo-products by selecting the appropriate ring-opening
method.
In conclusion, we have developed novel blue LED-induced
cyclopropanol formation reaction from a-ketoamides. This process
has the potential for the synthesis of highly substituted cyclo-
propanol derivatives bearing amide functionality. The correspond-
ing diradical-like precursor 11 appears to be generated by H-atom
abstraction by the amide group, which is the rate-determining
step, in contrast to the known Norrish-type II process of
the sterically less demanding isopropyl or ethyl a-ketoamide gave
messy mixtures, suggesting that close proximity between the
amide functionality and the reaction site is significant for this
transformation.
Chesta and Whitten reported that little kinetic isotope
effect (KIE) was observed in the reaction of N,N-disubstituted
a-ketoamides. Further investigations are in progress.
a-ketoamides 1 to give b-lactam derivatives 2 and/or oxazolidi-
none 3, even when the N -proton of the substrate 1 was replaced
a
Acknowledgements
with deuterium.8 These results indicated that H-atom abstraction
is not the rate-determining step in the photo-chemical reaction
of 1. On the other hand, significant KIE was observed in our
reaction. Photolysis of the mixture of 14f and 14f-d9 (1:1) gave a
mixture of 15f and 15f-d8 (2 h: yield 6%, KIE = 3.0; 8 h: yield 23%,
KIE = 3.1), clearly indicating that H-atom abstraction is involved
in the rate-determining step of the cyclopropanol formation
reaction (Scheme 3).
We would like to thank Prof. Kazuo Nagasawa (Tokyo Univer-
sity of Agriculture and Technology, Japan) and Prof. Kazunobu
Toshima (Keio University, Japan) for their kind support to this
research. This work was partially supported by Grants-in-Aid for
Scientific Research (No. 26102744). E.O. is a Research Fellow of
JSPS.
Finally, the ring-opening reaction of cyclopropanol 15f was
examined (Scheme 4). Treatment of 15f with allyl bromide in the
presence of Et2Zn and CuClꢁ2LiCl gave ring-opening product 21
with the allyl group at the more-substituted carbon in a site-
selective manner in moderate yields. It should be noted that this
was an unexpected result, since this condition was reported to
open the cyclopropanol ring and lead to the introduction of an allyl
unit via SN20 reaction at the less-hindered carbon center.20 The
amide group might contribute to the change of site-selectivity
Supplementary data
Supplementary data (additional figures and a table (Figs. S1–S8,
Schemes S1–S5, and Table S1), preparation of substrate
a
-ketoamides, characterization data for new compounds,
representative experimental procedures, and 1H and 13C NMR
spectra) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2015.09.038.

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E. Ota et al. / Tetrahedron Letters 56 (2015) 5991–5994
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