Photofluorination of Aliphatic C-H Bonds Promoted by the Phthalimide Group

Article abstract of DOI:10.1021/acs.orglett.8b00133

Aliphatic C-H fluorination of phthalimide derivatives with Selectfluor was investigated under photoirradiation conditions. The reaction did not require any additive or catalyst and afforded C-H fluorinated products in moderate to good yields. It is likely

Full text of DOI:10.1021/acs.orglett.8b00133

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Photofluorination of Aliphatic C−H Bonds Promoted by the
Phthalimide Group
Hiromichi Egami,* Shuya Masuda, Yuji Kawato, and Yoshitaka Hamashima*
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
*
S Supporting Information
ABSTRACT: Aliphatic C−H fluorination of phthalimide
derivatives with Selectfluor was investigated under photo-
irradiation conditions. The reaction did not require any
additive or catalyst and afforded C−H fluorinated products in
moderate to good yields. It is likely that the reaction site
depends on the C−H bond energy, and this may be the reason
for the good to high regioselectivity.
he amino group is found in many molecules, including
The incorporation of fluorine atom(s) is widely used to
T
naturally occurring bioactive compounds, pharmaceutical
drugs, and functional materials. A substitution reaction with
phthalimide is one of the methods available for the introduction
modify the activity or properties of the parent compounds in
6
pharmaceutical, agrochemical, and materials sciences. There-
7
fore, various fluorination methodologies have been developed.
1
of amino equivalents, as exemplified by the Gabriel reaction
Among them, C−H fluorination is of great interest from the
2
8
and Mitsunobu reaction. Consequently, the phthalimide unit
viewpoint of atom and step economy. The classical method-
can be found in various synthetic intermediates. Normally it is
used as a protecting group, and a deprotection step is necessary
at a later stage to provide the corresponding primary amine. In
contrast, the function of phthalimide as a photosensitizer has
been less well studied. In 1972, Kanaoka reported a
photocyclization reaction via C−H abstraction by a photo-
ology is to use molecular fluorine or CF OF under photo-
irradiation, and perfluorinated compounds are generally the
3
9
major products. Recent progress in this area has enabled more
selective C−H fluorination of simple benzylic and aliphatic
compounds with safer electrophilic fluorine sources in the
10,11
presence of metal catalysts or organocatalysts.
Also, a
3
excited phthalimide (Scheme 1a). Later, Mariano and Yoon
remarkable Norrish−Yang-type fluorination of polycyclic
12
terpenoid derivatives was recently reported by Lectka.
We have been working on fluorination and trifluoromethy-
Scheme 1. Photoexcitation of Phthalimide
13
lation reactions of C−C multiple bonds, and we have recently
1
4
focused on direct C−H fluoro-functionalizations. For
example, we reported C−H trifluoromethylation via the
formation of a photoenol as an active nucleophilic species
generated from a 2-methylbenzophenone derivative under
14b
photoirradiation conditions. These results prompted us to
examine the feasibility of using phthalimide derivatives in
photofluorination. In this report, we describe aliphatic C−H
photofluorination of phthalimide derivatives, in which the
phthalimide group plays a key role as an activating group
(
Scheme 1b). Although there are several C−H fluorination
reactions that are applicable to phthalimide derivatives, they
normally need a catalyst
of aliphatic compounds, in which anthraquinone was required
as a photosensitizer.
10d,f,i,j
Tan reported a C−H fluorination
10h
In order to optimize the reaction conditions, the reaction was
carried out with N-butylphthalimide 1a as a test substrate
(
Table 1). According to the literature, a suitable wavelength for
applied the photoexcitation of phthalimide to the generation of
azomethine ylides from phthalimide derivatives with a silicon-
containing electron donor. These studies led to the develop-
excitation of phthalimide (n−π*) was expected to be 320−340
nm. To our delight, the reaction in MeCN proceeded
15
4
ment of various transformations that are initiated by photo-
excited phthalimide-mediated C−H abstraction or single
Received: January 12, 2018
5
electron transfer.
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00133
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Substrate Scope
b
entry
solvent
hν (nm)
fluorinating reagent
yield of 2a (%)
c
1
2
3
4
5
6
7
8
MeCN
DMSO
365
365
365
365
395
425
365
365
365
−
3
3
3
3
3
3
4
5
6
3
3
78 (72)
0
CH Cl2
0
2
THF
0
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
67
0
77
0
9
0
d
1
0
1
0
e
c
1
365
71 (60)
a
The reactions were carried out with 1a and fluorinating reagent (1.2
b
equiv) on a 0.1 mmol scale, unless otherwise mentioned. Determined
by H NMR analysis using 1,1,2,2-tetrabromoethane as an internal
standard. Isolated yield. Run without photoirradiation. Run on a 1.0
mmol scale.
1
c
d
e
16
smoothly with an LED light source (365 nm), and fluorinated
product 2a was obtained in 78% yield (entry 1). DMSO,
CH Cl , and THF did not provide the desired fluorination
a
1
Determined by H NMR analysis using 1,1,2,2-tetrabromoethane as
an internal standard. The values in parentheses are isolated yields.
2
2
product (entries 2−4). Although photoirradiation at 395 nm
provided 2a in good yield (entry 5), 425 nm was not suitable
for this reaction (entry 6). Other fluorinating reagents were also
examined. Selectfluor II (4) was found to be as effective as
Selectfluor (3) (entry 7), while the reaction did not proceed at
all with 5 and 6 (entries 8 and 9). No transformation was
observed in the absence of photoirradiation (entry 10). Since
Selectfluor is less expensive than Selectfluor II, we chose
Selectfluor (3) as the fluorinating reagent. Gratifyingly, our
fluorination reaction could be scaled up without difficulty, and
b
The products could not be separated from the corresponding
substrates.
derivative 1j underwent C−H fluorination, a 1:1 diastereomeric
mixture was formed. Interestingly, 1k bearing an ethyl ester
reacted at the α-position of the oxygen atom to afford 1-
fluoroethyl ester 2k in 42% yield. In addition, glycine benzyl
ester 1l afforded the similar product 2l in 45% yield.
To shed light on the importance of phthalimide for this C−
H fluorination, we also examined the reactions of n-butylamine
derivatives with other protective groups. As shown in Scheme
3a, a nosyl group or a simple benzamide group did not work as
a photoactivator, and the fluorinated product was not detected
at all. In addition, a simple succinimide unit was completely
2
a was obtained in 71% yield even on a 1.0 mmol scale (entry
11). It is noteworthy that this reaction did not require any
additive or catalyst.
With the optimized reaction conditions in hand, we next
investigated the substrate scope of this fluorination reaction
17a
(Scheme 2). Propyl phthalimide (1b) was converted selectively
ineffective. As 4,5,6,7-tetrachlorophthalimide is also utilized
17
to β-fluorinated product 2b in 47% yield. In the case of pentyl
substrate 1c, the fluorination proceeded at both the γ- and δ-
positions, but the δ-position was more reactive (2c:2c′ = 3:1).
A tertiary carbon center could undergo the C−H fluorination,
and 2d was formed in 60% yield. The reaction of 1d was slower
than that of 1a, suggesting that steric hindrance might retard
this C−H fluorination kinetically. In accord with the general
reactivity profile, benzylic C−H bonds were more reactive.
Thus, fluorinated products 2e, 2f, and 2g were produced in
as an ammonia equivalent, we also examined the reaction of
1m. Although 1m alone did not react with 3, the corresponding
fluorination product 2m was obtained in the presence of
phthalimide 1n, which is also an unreactive substrate (Scheme
3b). These results clearly indicate that the phthalimide group
plays a crucial role in this C−H fluorination. If a hydrogen atom
transfer process, as seen in Kanaoka’s reaction (Scheme 1a), is
involved in our C−H fluorination, 1a would be expected to
undergo intramolecular radical−radical coupling in the absence
of 3, affording a cyclized compound. However, 1a was
completely recovered, when 1a was exposed to LED irradiation
(365 nm) without Selectfluor in MeCN. These results suggest
that the present C−H fluorination may require energy transfer
between phthalimide and Selectfluor, and indicate that
9
1%, 88%, and 98% yield, respectively. Because amino acid
10i
derivatives are of interest as feedstocks, we investigated
reactions of phthalimide-protected amino acid esters. Leucine
and valine derivatives were good substrates, affording 2h and 2i
in 65% and 95% yield, respectively. Although phenylalanine
B
DOI: 10.1021/acs.orglett.8b00133
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Preliminary Mechanistic Studies
think that this process may occur either in an intramolecular or
intermolecular fashion. At present, we cannot rule out the
possibility of intermolecular fluorine transfer to the generated
carbon radical from external Selectfluor and a radical chain
reaction mechanism. It seems likely that the reaction site
depends on the C−H bond energy, and phthalimide should
19
deactivate adjacent C−H bonds, accounting for the good site
selectivity of this reaction.
3
In summary, we have developed a method for C −H
sp
fluorination of N-alkyl phthalimide derivatives under photo-
irradiation conditions. The reaction proceeded selectively at not
only aliphatic but also benzylic positions, furnishing the
corresponding fluorinated compounds in good yields. The
importance of the phthalimide unit for this reaction was
demonstrated by control experiments with other protecting
groups, which proved ineffective. The reaction may proceed via
exciplex formation between Selectfluor and phthalimide.
Studies to establish the reaction mechanism and to develop
applications of this chemistry are in progress.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00133.
Typical experimental procedures and characterization of
products (PDF)
intramolecular hydrogen atom abstraction by the oxygen radical
of the triplet state of phthalimide does not occur.
Based on the above results and findings in the literature, we
AUTHOR INFORMATION
Corresponding Authors
■
*
*
18
E-mail: hamashima@u-shizuoka-ken.ac.jp.
E-mail: hegami@u-shizuoka-ken.ac.jp.
propose the reaction mechanism illustrated in Scheme 4. The
ORCID
Scheme 4. Proposed Mechanism
Yoshitaka Hamashima: 0000-0002-6509-8956
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by TORAY Award in Synthetic
Organic Chemistry, Japan, Grant-in-Aid for Scientific Research
(
B) (No. 16H05077), and Basis for Supporting Innovative
Drug Discovering and Life Science Research (BINDS) from
AMED.
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DOI: 10.1021/acs.orglett.8b00133
Org. Lett. XXXX, XXX, XXX−XXX