Fluoroalkylation of Various Nucleophiles with Fluoroalkyl Sulfones through a Single Electron Transfer Process

Article abstract of DOI:10.1021/acs.joc.9b00419

The fluoroalkylation of various nucleophilic reagents with (phenylsulfonyl)difluoromethyl (PhSO₂CF₂)-substituted phenanthridines was achieved to give fluorinated phenanthridine derivatives, which enables the construction of both carbon-heteroatom and carbon-carbon bonds via the substitution of the phenylsulfonyl group. Mechanistic studies indicated that these reactions proceed through a unimolecular radical nucleophilic substitution (S_RN1) mechanism. It is worthwhile noting that in the cases of O-nucleophiles (t-BuO^- and PhO^-), the addition of t-BuOK/PhCHO could significantly promote the reactions, due to the in situ formation of a highly reactive electron donor species through the interaction of t-BuOK, PhCHO, and the solvent DMF, which can effectively initiate the single electron transfer process.

Full text of DOI:10.1021/acs.joc.9b00419

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Featured Article
Fluoroalkylation of Various Nucleophiles with Fluoroalkyl
Sulfones Through a Single Electron Transfer Process
Pan Xiao, Chuanfa Ni, Wenjun Miao, Min Zhou, Jingyu Hu, Dingben Chen, and Jinbo Hu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00419 • Publication Date (Web): 14 May 2019
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Fluoroalkylation of Various Nucleophiles with Fluoroalkyl
Sulfones Through a Single Electron Transfer Process
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,‡
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Pan Xiao, Chuanfa Ni, Wenjun Miao, Min Zhou, Jingyu Hu, Dingben Chen,
,†,‡
and Jinbo Hu*
†
Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai
Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of
Sciences, 345 Ling-Ling Road, Shanghai 200032, China
‡
School of Physical Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai
2
01210, China
*E-mail: jinbohu@sioc.ac.cn
Table of Contents
Abstract: The fluoroalkylation of various nucleophilic reagents with
phenylsulfonyl)difluoromethyl (PhSO CF )-substituted phenanthridines was
(
2
2
achieved to give fluorinated phenanthridine derivatives, which enables the
construction of both carbonheteroatom and carboncarbon bonds via nucleophilic
substitution of the phenylsulfonyl group. Mechanistic studies indicated that these
reactions proceed through unimolecular radical nucleophilic substitution (S 1)
RN

mechanism. It is worthwhile noting that in the cases of O-nucleophiles (t-BuO and

PhO ), the addition of t-BuOK/PhCHO could significantly promote the reactions, due
to the in-situ formation of a highly reactive electron donor species through the
interaction of t-BuOK, PhCHO and the solvent DMF, which can effectively initiate
the single electron transfer (SET) process.
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Introduction
Recently, organofluorine chemistry has been a research field of great interest as
fluorine plays conspicuous and increasing important roles in pharmaceuticals,
1
,2
agrochemicals, as well as in materials science. Therefore, the quest for new reagents
and methodologies to efficiently introduce various fluorine-containing moieties into
structurally diverse non-fluorinated organic compounds makes this research area very
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attractive to scientists. Meanwhile, nitrogen-containing heterocycles are a class of
4
important chemical structures, among which the phenanthridine core is commonly
5
present in many biologically active and medicinally useful natural products. In
6
addition, some phenanthridine derivatives have been used as luminescent materials.
In this context, selectively incorporating organofluorine functionalities into
phenanthridine rings may significantly improve their biological activity and
1
c,2a,7,8
optoelectronic property due to the unique role of fluorine substitution.
Fluoroalkyl phenyl sulfones (R SO Ph) have been developed as versatile
f
2
fluoroalkylation reagents and used for introducing diverse fluoroalkyl groups into
9
-11
organic molecules by us and others.
It has been reported that R SO Ph can be
f 2
9
a
9b-f
converted to R TMS (TMS = trimethylsilyl) or R H
under the reduction of
f
f
magnesium. In the presence of alkoxide or hydroxide, R SO Ph can be attacked by
f
2
nucleophiles to remove the PhSO group and to give rise to fluoroalkyl carbanions,
2
which further react with electrophiles such as PhSSPh and PhCHO or are cuparated
1
0
by Cu(I) salt to generate R Cu. Furthermore, R SO Ph can be transformed to
f
f
2
11
fluorinated olefins under certain condtions. However, the use of R SO Ph for radical
f
2
fluoroalkylation by R SO Ph bond cleavage to form R • radicals is still
f
2
f
underdeveloped due to the weak electron-transfer ability of many conventional radical
1
2
initiators towards R SO Ph. Indeed, it is only in early 2016 that synthetically useful
f
2
radical fluoroalkylations with fluorinated sulfones were reported by the virtue of
1
3
heteroaryl sulfone reagents. Recently, we have disclosed a method to prepare
phenylsulfonyldifluoromethyl (PhSO CF )-substituted phenanthridines such as 1a
2
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(Scheme 1) by the process of radical fluoroalkylation with difluoromethyl phenyl
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sulfone (PhSO CF H). To expand the application of 1a and its derivatives, it is of
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great interest to further modify these compounds by developing new desulfonative
transformations. Herein, we report the radical difluoroalkylation reactions of
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-[difluoro(phenylsulfonyl)methyl]phenanthridines with various nucleophiles through
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unimolecular radical nucleophilic substitution (S 1) mechanism, which represent a
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new reaction mode of R SO Ph.
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Results and Discussion
. Initial results. Recently, we accomplished the substitution of PhSO group in
1
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1
a with PhS group using PhSSPh as the electrophilic reagent under the attack of
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t-BuOK (Scheme 1, eq 1), which was shown to proceed through a fluoroalkyl
10a-b
carbanion intermediate.
However, when PhCHO was used instead of PhSSPh as
an electrophile, it was surprising to observe that the O-fluoroalkylation product 3
rather than the expected alcohol 2 was formed (Scheme 1, eq 2). This unusual result
indicates that the reaction of 1a with t-BuOK and PhCHO did not involve a
fluoroalkyl carbanion intermediate. On the contrary, in the absence of PhCHO or any
other electrophiles, 1a underwent attack by t-BuOK and further reacted with another
14
molecule of itself to generate 4 (instead of 3) as the main product (Scheme 1, eq 3),
thus revealing that the addition of PhCHO plays an important role in the formation of
the O-fluoroalkylation product 3. Inspired by previous reports that a single electron
1
5
transfer (SET) pathway may be involved in the Cannizzaro reaction, we envisioned
that the reaction of 1a with t-BuOK in the presence of PhCHO may proceed through
an unimolecular radical nucleophilic substitution (S 1) process, where the
RN
combination of t-BuOK/PhCHO serves as the initiator. The unprecedented reactivity
of 1a towards potassium tert-butoxide demonstrated a proof of concept for the further
development of radical transformation of R SO Ph with a series of nucleophiles. To
f
2
our knowledge, there has been no report describing the S 1 reaction between a
RN
fluoroalkyl sulfone and a nucleophilic reagent. Previously, fluoroalkyl halides rather
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than fluoroalkyl sulfones were normally used for the fluoroalkylation of nucleophilic
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reagents.
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Scheme 1. Desulfonative transformations of 1a.
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. Alcoholates as nucleophiles. Our investigation for the desulfonative
fluoroalkylations started from the optimization of the reaction conditions for the
generation of compound 3 by using 1a as substrate, t-BuOK as nucleophile, PhCHO
as additive, and DMF as solvent, respectively (Table 1). When the molar ration of 1a:
t-BuOK: PhCHO was 1.0: 2.0: 1.0, we examined the effect of temperature on the
reaction. As is shown in Table 1, it is clear that the starting temperature significantly
affected the reaction. The yield of 3 decreased significantly as the starting temperature
o
o
was elevated to room temperature, and temperatures between 60 Cand50 C were
the optimal starting temperatures for the reaction (Table 1, entries 1-4). When
t-BuONa was used instead of t-BuOK as the nucleophile, the reaction became very
sluggish, which revealed the importance of the countercation effect in the reaction
(Table 1, entry 5). Subsequently, we screened the equivalents of t-BuOK and found
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a
Table 1. Optimization of reaction conditions for the formation of 3.
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b
Reaction conditions: 1a (0.1 mmol), DMF (0.8 mL), under argon atmosphere. Yields
were determined by F NMR spectroscopy using PhOCF as an internal standard.
t-BuOK/DMF (1.0 M) was prepared by dissolving t-BuOK in DMF, and was then
19
3
c
d
added dropwise into the reaction system. t-BuONa/DMF (1.0 M) was used.
that 2.5 equiv of t-BuOK was optimal for the formation of 3 (Table 1, entries 1, 6-8).
In addition, the amounts of PhCHO could also affect the reaction significantly, with
1.0 equiv being the optimal amount (Table 1, entries7, 9-12). It is noteworthy that the
desired O-fluoroalkylation reaction was very sluggish in the absence of PhCHO
(
Table 1, entry 9), thus demonstrating that PhCHO plays a crucial role in the
generation of 3.
We also investigated the influence of other carbonyl compounds by replacing
PhCHO with additives including aromatic aldehydes, aliphatic aldehydes and
aromatic ketones (Table 2). Compared with PhCHO (Table 2, entry 1), electron-rich
aromatic aldehydes (Table 2, entries 2-6), benzaldehydes bearing weak
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electron-withdrawing groups (Table 2, entries 7-8), and 2-naphthaldehyde (Table 2,
entry 13) had relatively small effect on the reaction. However, 1,4-phthalaldehyde
(Table 2, entry 9) and benzaldehydes with strong electron-withdrawing groups such as
-
NO and -CN (Table 2, entries 10-12) remarkably decreased the yields of 3. In
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Table 2. Optimization of reaction conditions for the formation of 3.
a
Reaction conditions: 1a (0.1 mmol), aldehyde (1.0 equiv), t-BuOK (2.5 equiv), DMF
b
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(0.8 mL), under argon atmosphere. Yields were determined by F NMR
spectroscopy using PhOCF as an internal standard.
3
addition to aromatic aldehydes, cinnamaldehyde could also give rise to moderate yield
(Table 2, entry 14), but isobutyraldehyde could only afford a low yield of product
(Table 2, entry 15). When benzophenone was used instead of PhCHO, the reaction
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proceeded in quite low efficiency (Table 2, entry 16). In general, among all the
carbonyl compounds examined, PhCHO was identified to be the most effective
additive (Table 2, entry 1).
However, the “hard” nature of alkoxides (such as tert-butoxide) could lead to the
competitive consumption of the starting material 1a by the nucleophilic attack of an
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alkoxide towards PhSO , which restricted the improvement of the yield of the
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O-fluoroalkylation product. In our case, a full consumption of sulfone 1a led to the
desired product 3 only in moderate yield even under the optimized conditions, where
the remainder of the mass balance was attributed to the unidentified decomposition of
1
a as well as the formation of trace amounts of 6-(difluoromethyl)phenanthridine and
compound 4. Moreover, the yield of 3 decreased significantly (Scheme 2) when the
reaction was scaled up from 0.1 mmol scale to 0.2 mmol scale probably due to the
increasingly competitive nucleophilic attack of tert-butoxide towards PhSO to
2
–
release ArCF .
2
Scheme 2. The synthesis of 3 from 1a and t-BuOK.
To overcome the above-mentioned limitations of the substitution reaction of 1a
with alkoxides (such as t-BuOK), we turned our attention to the use of “soft”
nucleophiles with the hope that we can develop more effective S 1 transformations
RN
of 1a. Indeed, in 1974, Kornblum and co-workers reported the substitution reactions
of α-nitro sulfone with several soft carbon nucleophiles via SET process, which
1
7
encouraged us to pursuit the nucleophilic reactions with fluoroalkyl sulfones.
. Phenolates as nucleophiles. Phenolates has been used for the smooth
displacement of the halogen atom (X) of fluoroalkyl halides (R -X; X = I, Br, Cl)
3
f
1
6d-f
under additive-free conditions;
however, PhONa failed to react with 1a under
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similar conditions, even at elevated temperatures (Table 3, entries 1-3), indicating that
the direct electron transfer from phenoxide ion to 1a is inefficient. Considering that
the addition of PhCHO could promote the reaction between 1a and t-BuOK, we tried
the reaction between 1a and PhONa in the presence of t-BuOK and PhCHO. To our
delight, when t-BuOK (1.0 equiv) and PhCHO (1.0 equiv) were added, the reaction
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proceeded smoothly at room temperature and the desired product 6a was observed in
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8% F NMR yield (Table 3, entry 4). A screening of the amount of PhONa showed
that 3.0 equiv are optimal for the reaction (Table 3, entries 5-6). In the
above-mentioned conditions, t-BuOK was added in solid form. An optimization of the
experimental procedures showed that the dropwise addition of the DMF solution of
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t-BuOK could result in a much higher yield of 6a (> 99% yield based on F NMR, 93%
yield after isolation) than the addition of the t-BuOK solid in one portion (88% yield
a
Table 3. Optimization of reaction conditions for the formation of 6a.
a
b
Reaction conditions: 1a (0.1 mmol), DMF (1.0 mL), under argon atmosphere. Yields
1
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c
were determined by F NMR spectroscopy using PhOCF as an internal standard. A
DMF solution of t-BuOK was added dropwise into the reaction system. Reaction
conditions: 1a (0.2 mmol), DMF (2.0 mL), under argon atmosphere. Isolated yield.
3
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based on F NMR) (Table 3, entries 5 and 7). Control experiments in the presence of
either t-BuOK or PhCHO afforded the product 6a in only trace to low yields,
demonstrating that the interaction between t-BuOK and PhCHO plays a crucial role
(
Table 3, entries 8 and 9).
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a,b
Table 4. The substitution reactions of 1a with phenol derivatives 5.
a
Reaction conditions: 1a (0.2 mmol), 5 (2.7 equiv), t-BuOK (3.6 equiv), PhCHO (1.0
equiv), DMF (2.0 mL), under argon atmosphere, 12 h (unoptimized reaction time).
Isolated yields. Reaction conditions: 1a (0.2 mmol), PhONa (3.0 equiv), t-BuOK
1.0 equiv), PhCHO (1.0 equiv), under argon atmosphere. Contaning 4% of side
product 2. Isolated yield was given by recrystallization. Yield was determined by F
NMR spectroscopy using PhOCF as an internal standard.
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Encouraged by the above results, we investigated the scope of the phenolate
nucleophiles by slightly modifying the optimized reaction conditions shown in entry 7
of Table 3. Although phenolates can be used as isolated reagents, we chose phenols 5
as the pronucleophiles due to their ready availability; meanwhile, t-BuOK was used as
both the base for deprotonation and one of the components of the initiator (Table 4).
The reaction proved to be general and amenable to a range of structurally diverse
phenols 5, and the desired products 6 were obtained in moderate to excellent yields.
We found that the electronic nature of the phenols can significantly affect the reaction,
with the electron-rich phenols (6b-6i) being more reactive than the electron-deficient
one (6l). In the cases of methyl-substituted phenols, the substitution site of methyl had
little influence on the outcome (6d-6f); whereas in the cases of methoxy-substituted
phenols, the para-substituted one (6g) was found to be more reactive than the
meta-substituted one (6h). It is of note that some phenols with a halogen substituent
are also viable pronucleophiles in the current reaction (6j and 6k), probably due to the
π-electron-donating (resonance) effect of the halogen atom. In most cases, the
decrease of the yields probably arose from the side reaction of 1a induced by t-BuOK.
Interestingly, when the salt of an antioxidant, butylated hydroxytoluene (BHT) was
used as the nucleophilic reagent, the C-alkylation product 7 was isolated in 78% yield.
Moreover, the same reaction proceeded smoothly even in the absence of PhCHO
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(Scheme 3, eqs 1 and 2). Here, the extremely electron-rich phenolate anion derived
from BHT serves as the reducing agent, which transfers a single electron to 1a to
afford a difluoroalkyl radical (ArCF •) and an aryloxy radical (ArO•). The following
2
step may proceed either through the combination of two radicals or through an SRN1
mechanism, where the C-alkylation selectivity can be explained by the steric
hindrance of the aryloxy radical or anion.
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9
Scheme 3. The substitution reaction of 1a with BHT.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
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4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4. Thiolates and selenolates as nucleophiles. Thiolate and selenolate anions are
softer nucleophiles than alcoholate and phenolate anions. On the basis of the
successful reaction of 1a with a wide variety of phenolates, we further explored the
reactivity of 1a towards thiolates and selenolates.
The reaction of PhSNa and 1a in a molar ratio of 1:2 in DMF was chosen as the
model reaction (Table 5). It was found that the displacement of PhSO group with PhS
2
group could readily occur at room temperature in the absence of any additive (Table 5,
entry 1), which can be attributed to the strong single electron-donating ability of PhS
endowed by the high electronic polarizability of sulfur atom. A quick optimization of
the reaction conditions showed that there are two viable methods for improving the
o
yields of 9a: raising the reaction temperature from room temperature to 110 C (Table
5
4
, entry 3) or increasing the amount of PhSNa from 2 equiv to 4 equiv (Table 5, entry
); the latter method can lead to slightly higher yield of 9a.
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a
Table 5. Optimization of reaction conditions for the formation of 9a.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
b
Reaction conditions: 1a (0.1 mmol), DMF (1.0 mL), under argon atmosphere. Yields
1
9
were determined by F NMR spectroscopy using PhOCF as an internal standard.
3
After achieving the fluoroalkylation of PhSNa with 1a, we investigated the scope
of the thiolate nucleophiles (Table 6). For convenience, the thiolates were in situ
prepared by deprotonation of the corresponding thiols with NaH (95%) or t-BuOK.
When 2-mercaptopyridine was used as the pronucleophile, we found that DMSO was
superior to DMF in respect to promoting the reaction (9b). Therefore, in the
subsequent investigation, DMSO was used as the solvent to conduct the reactions of
1
a with thiolates. For most of the thilolates tested, their reactions proceeded smoothly
to afford 9 in moderate to excellent yields (9a-9h). Electron-neutral aryl substituted
thiolates such as PhSNa and 2-naphthalenethiol exhibited the highest reactivity (9a
and 9c); whereas the substitution of thiophenolate with a weak electron-withdrawing
group (EWG) such as F, Cl and Br, slightly decreased the efficiency of the reaction
(
9d-9f). However, further enhancing the electron-withdrawing ability of the
substituent on the thiophenolates by incorporating CF or five fluorine atoms
3
dramatically or even completely inhibited the reaction (9k and 9l) due to the
decreased single electron donating ability of the thiloates, as is indicated by the low
conversion of 1a. Similarly, para electron-donating groups (EDG) such as MeS, MeO,
and t-Bu also showed inhibition effect on the desired reaction (9g, 9i and 9j).
However, MeS group showed less significant influence than MeO and t-Bu groups. In
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9
the cases of MeO- and t-Bu-substituted thiolates, the low yields of 9 mainly arose
from the decomposition of 1a. In addition, a benzylmercaptan could also take part in
the reaction, albeit affording product 9h in only moderate yield.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
Table 6. The substitution reactions of 1a with thiolates.
a
Reaction conditions: 1a (0.2 mmol), 8 (4.0 equiv), NaH (4.0 equiv), DMSO (2.0 mL),
b
c
under argon atmosphere. Isolated yields. Reaction conditions: 1a (0.2 mmol), PhSNa
d
(4.0 equiv), DMF (2.0 mL), under argon atmosphere. Reaction conditions: 1a (0.2
mmol), 2-PySH (3.5 equiv), t-BuOK (4.4 equiv), PhCHO (1.0 equiv), DMSO (2.0
e
19
mL), under argon atmosphere, 72 h. Yields were determined by F NMR
spectroscopy using PhOCF as an internal standard.
3
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9
1
1
1
1
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Selenolates are also viable nucleophilic reagents. The fluoroalkylation of PhSeNa
18
that was in-situ generated from the reduction of PhSeSePh with NaH afforded the
desired product 10 in 78% isolated yield by conducting the reaction of 1a, PhSeSePh
and NaH in a molar ratio of 1:4:8 in DMF (Scheme 4).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 4. The substitution reaction of 1a with in situ generated PhSeNa.
5
. The salts of diethyl malonate derivatives as nucleophiles. A screening of
carbon nucleophiles showed that the salts of monosubstituted diethyl malonates could
react with 1a efficiently, thus consisting a new protocol for the construction of FCC
bonds with the displacement of the sulfonyl group. We compared the reactivity of
several α-monosubstituted diethyl malonates 11 towards 1a with t-BuOK as the base
and DMSO as the solvent, and found that the steric hindrance of 11 had a remarkable
effect on this reaction (Table 7). The reaction of 1a with the potassium salt of
CH CH(COOEt) (11a) proceeded smoothly in 12 h and the desired product 12aa was
3
2
obtained in 94% yield. However, the reaction rate declined gradually as the steric
hindrance of pronucleophiles 11 increased and a reaction time of 24 h was needed to
achieve a full conversion of the potassium salts of 11b and 11c (12ab, 12ac). In the
case of pronucleophile 11d with an α-benzyl substituent, much longer reaction time
(72 h) was required to complete the reaction (12ad). The diethyl malonate derivatives
bearing more sterically hindered α-substituents such as i-Pr, COOEt and COCH3
could not undergo this reaction. Moreover, the salt of nonsubstituted diethyl malonate
also failed to react with 1a, probably arising from its poor single electron-donating
ability.
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9
Table 7. The substitution reactions of 1a with the salts of diethyl malonate
a,b
derivatives 11.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
Reaction conditions: 1a (0.2 mmol), 11 (4.0 equiv), t-BuOK (4.0 equiv), DMSO (2.0
b
mL), under argon atmosphere. Isolated yields.
We also investigated the scope of PhSO CF -substituted phenanthridines by using
2
2
CH CH(COOEt) (11a) as a representative pronucleophile, and found that a variety of
3
2
1
4
previously prepared 6-[difluoro(phenylsulfonyl)methyl]phenanthridine derivatives
1a-1j) bearing either electron-withdrawing or electron-donating groups could be
(
transformed into the corresponding products 12 in excellent yields (Table 8). This
desulfonative difluoroalkylation reaction tolerates various functional groups on 1,
such as sulfonyl, trifluoromethyl, methyl, phenyl, fluoride, and chloride. In the cases
of sulfonyl-, fluoro- and chloro-substituted phenanthridines that were susceptible to
undergo nucleophilic aromatic substitution (S Ar), the reaction only took place at the
N
PhSO CF group.
2
2
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a,b
Table 8. The Substitution Reactions of 1 with the Salt of 11a.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
Reaction conditions: 1 (1.0 equiv), 11a (4.0 equiv), t-BuOK (4.0 equiv), DMSO,
b
under argon atmosphere. Isolated yields.
6. The salt of 2-nitropropane as nucleophile. 2-Nitropropane (13a) could be
deprotonated by t-BuOK and then reacted with 1a to give the corresponding product
14a. However, the relatively low solubility of the in situ generated potassium salt of
13a in DMSO led to a slow reaction rate at room temperature, thus the desired
1
9
product 14a was observed in a quite low yield (29% based on F NMR spectroscopy)
after 24 h. We found that the addition of 18-crown-6 could effectively improve the
yield of 14a, and we obtained 14a in 75% isolated yield when 2.4 equiv of
1
8-crown-6 were used (Scheme 5, eq 1). On this basis, we further explored the
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9
reaction of 1a with nitrocyclohexane (13b) at room temperature. The result turned out
to be unsatisfactory, with only 30% yield of the desired product 14b being observed
1
9
by F NMR spectroscopy even when the reaction time was prolonged to 48 h
Scheme 4, eq 2). The significant drop of the yield reveals that increased steric
(
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
hindrance was detrimental to the substitution reaction.
Scheme 5. The substitution reactions of 1a with the salt of niroalkanes 13.
7
. Mechanistic investigations. To gain more insights into the present
desulfonative fluoroalkylation reaction, we carried out mechanistic investigations.
Firstly, to probe the possibility of a radical mechanism, we tested the retarding
effect of several radical inhibitors on the standard reactions of 1a with various
nucleophiles. The results are summarized in Table 9 and Tables S1-S5 (See the
Supporting Information).
As is shown in Table 9, the reaction of 1a with t-BuOK was largely or
completely inhibited by single electron transfer inhibitors such as m-dinitrobenzene
and
p-dinitrobenzene,
and
free
radical
scavengers
such
as
2
,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and O . The reaction of 1a with
2
PhONa in the presence of t-BuOK/PhCHO was retarded similarly (See Supporting
Information, Table S1). Taken together with our initial understanding on the role of
t-BuOK/PhCHO, we believed that the reaction proceeded through a SET chain
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9
1
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1
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2
2
2
2
2
2
2
2
2
3
3
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3
3
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4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
process that was initiated by an electron donor species related to PhCHO (Scheme 6).
Initially, “electron donor A” that is formed by the interaction of t-BuOK/PhCHO acts
the initiator and donates a single electron to 1a to generate the radical anion B. Then
the resulting radical anion B undergoes a fragmentation to release difluoroalkyl
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0


radical C and PhSO . Subsequently, the combination of C with a nucleophile (Nu =
2


t-BuO , PhO ) leads to the formation of a new radical anion D. Finally, intermediate
D transfers a single electron to another molecule of 1a to produce the product 15 and
regenerate intermediate B.
a
Table 9. Control Experiments of 1a with t-BuOK.
a
Reaction conditions: 1a (0.1 mmol), PhCHO (1.0 equiv), t-BuOK/DMF (1.0 M)
b
19
(
0.25 mL), DMF (0.8 mL), under argon atmosphere. Yields were determined by F
NMR spectroscopy using PhOCF as an internal standard.
3
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Scheme 6. Plausible mechanism of the reaction of 1a with t-BuOK (or PhONa).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Radical inhibition experiments (See the Supporting Information, Tables S2-S5)
also support a S 1 mechanism in the reactions of 1a with other nucleophilic species
RN




(
PhS , PhSe , CCH (COOEt) and C(CH ) NO ) (Scheme 7). In these cases, the
3 2 3 2 2
nucleophiles itself can act as the initiators to trigger the propagation step. The radicals
derived from these nucleophiles should end up with homocoupling reaction.
Scheme 7. Plausible mechanism of the reaction of 1a with other nucleophiles.
Secondly, to understand the exact role of light, we conducted the control
experiments both under room light illumination and in the dark (See the Supporting
Information, Tables S1-S5). It was found that room light illumination is necessary in
the reactions of PhSNa, PhSeNa, and a malonate salt KC(Me)(CO Et) with the
2
2
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1
1
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2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
5
6
sulfone 1a (Tables S2-S4). The same reactions in the absence of room light were
found to be very sluggish. The promoting role of room light can be explained by the
–
formation of a charge-transfer complex (CTC) of 1a and the nucleophile (Nu ) and its
·–
19
subsequent activation by the visible light to afford 1a and Nu·.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
However, when PhONa was used as the nucleophile (with tBuOK/PhCHO/DMF
as the initiator) (Table S1), the reaction in DMF completed in 1 hour, giving the
desired product in high yield both in the presence and the absence of the light. This
indicates that room light has little influence on the reaction of phenolates.
Thirdly, to figure out the possible initiator in the reaction of 1a with t-BuOK or
PhONa, we investigated the roles of both the intermediates and the possible final
products that are related to the Cannizzaro reaction between t-BuOK and PhCHO
(Table 10). To evaluate the role of the Cannizzaro reaction intermediates, the mixture
of t-BuOK and PhCHO in DMF was pre-stirred for 1 h or 2 h before adding 1a.
However, the thus formed reaction mixture could also promote the reaction of
t-BuOK with 1a smoothly, albeit with slightly lower yields (Table 10, entries 2-3),
indicating that the initiator might be the final products rather than the intermediates.
Accordingly, we replaced PhCHO with PhCH OH and PhCO t-Bu (the main products
2
2
of the Cannizzaro reaction of PhCHO), respectively, and found that the reaction yield
was remarkably decreased (Table 10, entries 4-5). Also, PhCO H resulting from either
2
the autoxidation of PhCHO or hydroxide promoted Cannizzaro reaction of PhCHO
could not promote the reaction (Table 10, entries 5-6). Thus, we ruled out the
participation of either the intermediates or the final products of the Cannizzaro
reaction in triggering the SET process. The participation of benzoin condensation is
also unlikely, as the formation of 3 was not observed when benzoin was used instead
of PhCHO (Table 10, entry 7).
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a
Table 10. The study of intermediates in the reaction system of 1a with t-BuOK.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
Reaction conditions: 1a (0.1 mmol), PhCHO (1.0 equiv), t-BuOK/DMF (1.0 M)
b
19
(
0.25 mL), DMF (0.8 mL), under argon atmosphere. Yields were determined by F
NMR spectroscopy using PhOCF as an internal standard.
3
Recently, Murphy and coworkers made an elegant investigation on t-BuOK
promoted SET processes and disclosed that the dimerization of formamides can afford
2
0
strong organic electron donors such as G and H (Scheme 8, eq 1) , which inspired us
to take into account the combinational effect of t-BuOK, PhCHO and DMF in our
reaction system. We envisioned that the addition of the acyl anion derived from DMF
to PhCHO followed by proton transfer should lead to the generation of electron donor
A , and further deprotonation of A should afford A with stronger electron-donating
1
1
2
ability (Scheme 8, eq 2). To confirm this assumption, we separately prepared the
precursor of intermediate I, α-hydroxyl amide 16 by reacting PhCHO and DMF with
2
1
LDA as the base (Scheme 8, eq 3) and examined its influence on the reaction of 1a
with t-BuOK and PhONa, respectively (Tables 11 and 12). Gratifyingly, by using 16
instead of PhCHO, the reaction of 1a with t-BuOK afforded 3 in 47% yield when 0.4
equiv of 16 was loaded (Table 11, entry 4). For the reaction system of PhONa, only
0
1
.2 equiv of 16 was needed to achieve an excellent conversion of 1a (Table 12, entries
-3). In addition, t-BuOK also played an important role in the reaction, as is
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5
5
6
Scheme 8. Possible structure of “electron donor A”.
0
1
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7
8
9
0
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3
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7
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7
8
9
0
a
Table 11. The effect of compound 16 on the reaction of 1a with t-BuOK.
a
Reaction conditions: 1a (0.1 mmol), DMF (0.8 mL), under argon atmosphere.
t-BuOK (1.0 M in DMF) was prepared by dissolving t-BuOK in DMF just before the
b
c
reaction and was then dropped slowly into the reaction system. Yields were
1
9
determined by F NMR spectroscopy using PhOCF as an internal standard.
3
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demonstrated by the dramatic decrease of the yield of 6a when less than 1 equiv of
t-BuOK was used (Table 12, entries 3-5). It is clear that t-BuOK not only promoted
the deprotonation of 16 to generate intermediate I (Scheme 8), but also facilitated the
formation of enolate A and dianion A , which should serve as key electron donors in
1
2
1
1
1
1
1
1
1
1
1
1
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2
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5
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5
5
5
6
0
1
2
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4
5
6
7
8
9
0
1
2
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4
5
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7
8
9
0
1
2
3
4
5
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8
9
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5
6
7
8
9
0
1
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8
9
0
20
the reaction system.
a
Table 12. The effect of compound 16 on the reaction of 1a with PhONa.
a
Reaction conditions: 1a (0.1 mmol), PhONa (3.0 equiv), DMF (1.0 mL), under argon
b
19
atmosphere. Yields were determined by F NMR spectroscopy using PhOCF as an
3
internal standard.
Finally, to investigate the influence of the π-system connecting to the
difluoromethylene group on the single electron transfer process, we conducted the
reaction of 2-PyCF SO Ph and PhCF SO Ph with the most challenging nucleophile
2
2
2
2
t-BuOK. Interestingly, none of them could undergo the desired nucleophilic
substitution reaction, indicating that a large conjugated structure is beneficial for the
reaction. We also measured the first reduction potentials of the phenanthridine
derivative 1a (–1.20 V vs. SCE), 2-PyCF SO Ph (–1.44 V vs. SCE), and PhCF SO Ph
2
2
2
2
(–1.55 V vs. SCE) by cyclic voltammetry (CV) and found that the single electron
transfer reactivity of 1a towards t-BuOK is consistent with its highest first reduction
2
2
potential.
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5
6
Conclusions
In summary, we have developed the desulfonative fluoroalkylation of various
nucleophiles with 6-[difluoro(phenylsulfonyl)methyl]phenanthridine and its
derivatives, leading to the formation of new carbonheteroatom bonds and
carboncarbon bonds with the removal of the sulfonyl group. A process of single
electron transfer is likely to be involved in our reaction system. In particular, the
interaction of t-BuOK, PhCHO and DMF might facilitate the formation of “electron
donors”, which then initiate the reaction between the substrate and the nucleophiles
such as t-BuOK and PhONa which are difficult to donate a single electron.
0
1
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9
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9
0
Experimental Section
General Methods. Unless otherwise mentioned, all manipulations were
conducted with a standard Schlenk tube under argon atmosphere, and reagents were
purchased from commercial sources and used without further purification. Dry DMF
and DMSO were distilled over CaH , and stored over activated molecular sieves.
2
1
NMR spectra were obtained on a Bruker AV400 or Agilent MR400 (400 MHz for H;
19
13
1
376 MHz for F; 100 MHz for C). H NMR chemical shifts were determined
relative to internal (CH ) Si (TMS) at : δ 0.00 ppm or to the signal of a residual
3 4
1
3
protonated solvent: CDCl : δ 7.26 ppm. C NMR chemical shifts were determined
3
1
13
19
relative to internal CDCl at : δ 77.0 ppm. H, C and F multiplicities are reported
3
as follows: singlet (s), doublet (d), triplet (t), quartet (q), doublet of doublets (dd),
triplet of quartets (tq), multiplet (m), and broad resonance (br). All the melting points
were uncorrected. Mass spectra were obtained on a mass spectrometer.
High-resolution mass data were recorded on a high-resolution mass spectrometer in
the ESI mode.
Preparation
-(Difluoro(phenylsulfonyl)methyl)phenanthridine Derivatives 1. All the
compounds 1a-1i (for a list, see the Supporting Information) are known and prepared
of
Starting
Material
6
1
4
according to our reported procedures. Compounds 1b-1i were prepared on 0.2 mmol
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scale in similar yields as previously reported. Compound 1a was prepared on gram
scale by a modification of the purification procedure as follows:
To an oven-dried 300 mL Schlenk Tube were added (diacetoxyiodo)benzene
(
17.8766 g, 55.5 mmol, 6.0 equiv) and cesium carbonate (3.0138 g, 9.25 mmol, 1.0
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
equiv) in glove box. Under argon atmosphere, iodine (I , 469.5 mg, 1.85 mmol, 0.2
2
equiv) was added quickly and DMF (40 mL) was injected into the flask. The reaction
o
o
mixture was stirred, and then the tube was cooled to 50 C ~ 60 C with dry
ice/acetone cold bath. After the addition of difluoromethyl phenyl sulfone (3.5550 g,
1
2
8.5 mmol, 2.0 equiv), a DMF (15 mL) solution of sodium tert-butoxide (2.6665 g,
7.75 mmol, 3.0 equiv) was added dropwise into the reaction system. Then a DMF
(
10 mL) solution of 2-isocyano-1,1'-biphenyl (1.6579 g, 9.25 mmol, 1.0 equiv) was
injected with a syringe, followed by the slowly addition of another portion of sodium
tert-butoxide (2.6665 g, 27.75 mmol, 3.0 equiv) in DMF (15 mL). The resulting
o
o
reaction mixture was stirred at 50 C ~ 60 C under Ar atmosphere for 2 h. Then
the mixture was warmed to room temperature and water (150 mL) was added. The
aqueous layer was extracted with ethyl acetate (EtOAc) (150 mL × 3) and the
combined organic layer was dried over anhydrous MgSO . After the solution was
4
filtered, the solvent was evaporated under reduced pressure and the residue was mixed
with silica gel and preliminarily purified by column chromatography on silica gel by
using PE/EtOAc as eluent (20:1~5:1, v/v) to provide crude product of 1a, which was
further recrystallized with EtOAc/petroleum ether (PE) to provide 1a as white crystals
o
1
(
1.4692g, 43%). M.p. 144 146 C. H NMR (400 MHz, CDCl ) : δ 8.69 (t, J = 8.8
3
Hz, 2H), 8.61 – 8.59 (m, 1H), 8.29 – 8.13 (m, 1H), 8.09 (d, J = 7.8 Hz, 2H), 7.91 (t, J
1
9
=
7.6 Hz, 1H), 7.80 – 7.74 (m, 4H), 7.61 (t, J = 7.8 Hz, 2H). F NMR (376 MHz,
CDCl ) : δ 95.7 (s, 2F). All the characterization data are consistent with previous
3
14
report.
Procedures
-(tert-Butoxydifluoromethyl)phenanthridine (3) (Scheme 2). To an oven-dried 10
mL Schlenk Tube was added 6-(difluoro(phenylsulfonyl)methyl)phenanthridine (1a)
73.9 mg, 0.2 mmol, 1.0 equiv) and then the flask was evacuated and backfilled with
for
the
Preparation
of
6
(
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1
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1
1
2
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2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
4
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5
5
5
5
5
5
5
5
6
argon for 3 times. PhCHO (21.2 mg, 0.2 mmol, 1.0 equiv) mixed with DMF (1.6 mL)
was added via syringe in one portion. The reaction mixture was stirred, and then the
o
o
tube was cooled to 50 C ~ 60 C with dry ice/acetone cold bath. A DMF solution
of t-BuOK (1.0 mol/L, 0.5 mL, 0.5 mmol), which was prepared just before the
experiment, was added dropwise into the reaction system. The resulting reaction
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
o
mixture was stirred at 50 C ~ 60 C under Ar atmosphere for 3 h and was stirred
further at room temperature for 14 h. After the reaction was complete, the mixture
was quenched with H O (5 mL). The aqueous layer was extracted with EtOAc (8 mL
2
×
3) and the combined organic layer was dried over anhydrous MgSO . After the
4
solution was filtered, the solvent was evaporated under reduced pressure and the
residue was mixed with silica gel and purified by column chromatography on silica
gel by using PE/EtOAc (40:1 ~20:1, v/v) as eluent to provide 3 as pale yellow solid
o
1
(
28.9 mg, 48%). M.p. 59 61 C. H NMR (400 MHz, CDCl ) : δ 8.65 (d, J = 8.0 Hz,
3
1H), 8.58 (t, J = 7.0 Hz, 2H), 8.29 (d, J = 8.0 Hz, 1H), 7.86 (t, J = 7.8 Hz, 1H), 7.78 –
1
9
13
1
7.70 (m, 3H), 1.66 (s, 9H). F NMR (376 MHz, CDCl ) : δ 63.8 (s, 2F). C{ H}
3
NMR (100 MHz, CDCl ) : δ 151.3 (t, J = 33.1 Hz), 142.0, 134.1, 131.0, 130.7, 129.0,
3
128.3, 127.6, 127.3, 125.0, 122.5, 122.2, 122.0, 121.9 (t, J = 264.2 Hz), 83.3, 30.4 (t,
J = 1.9 Hz). IR (KBr): 3084, 2994, 2929, 1579, 1469, 1372, 1247, 1183, 1165, 1152,
-1
+
1
120, 1046, 1028, 968, 884, 758, 729, 717 cm . MS (ESI, m/z): 302.1 (M+H ).
+
+
HRMS (ESI): Calcd. for C H F NO (M+H ): 302.1351, found: 302.1349.
18 18
2
Procedures
for
the
Preparation
of
6
-(Difluoro(phenoxy)methyl)phenanthridine (6a) (Table 4). To an oven-dried 10
mL Schlenk Tube was added 6-(difluoro(phenylsulfonyl)methyl)phenanthridine (1a)
73.9 mg, 0.2 mmol, 1.0 equiv) and PhONa (69.7 mg, 0.6 mmol, 3.0 equiv) in glove
(
box. Then the flask was moved out of the glove box and was evacuated and backfilled
with pure argon for 3 times. PhCHO (21.2 mg, 0.2 mmol, 1.0 equiv) in DMF (1.0 mL)
was added via syringe in one portion. The reaction mixture was stirred, and then a
DMF (1.0 mL) solution of t-BuOK (22.4 mg, 0.2 mmol, 1.0 equiv), which was
prepared just before the experiment, was added dropwise into the reaction system.
The resulting reaction mixture was stirred at room temperature and room light
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illumination under argon atmosphere for 12 h. After the reaction was complete, the
mixture was quenched with H O (5 mL). The aqueous layer was extracted with
2
EtOAc (8 mL × 3) and the combined organic layer was dried over anhydrous MgSO4.
After the solution was filtered, the solvent was evaporated under reduced pressure and
the residue was mixed with silica gel and purified by column chromatography on
silica gel by using PE/EtOAc (100:1 ~ 80:1, v/v) as eluent to provide 6a as white
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
1
solid (59.5 mg, 93%). M.p. 77 79 C. H NMR (400 MHz, CDCl ) : δ 8.68 (t, J =
3
6
7
.8 Hz, 2H), 8.61 – 8.59 (m, 1H), 8.33 – 8.31 (m, 1H), 7.92 – 7.88 (m, 1H), 7.82 –
19
.74 (m, 3H), 7.43 – 7.36 (m, 4H), 7.25 – 7.21 (m, 1H). F NMR (376 MHz, CDCl ) :
3
13
1
δ 67.8 (s, 2F). C{ H} NMR (100 MHz, CDCl ) : δ 150.6, 149.4 (t, J = 31.6 Hz),
3
1
1
1
42.0, 134.2, 131.23, 131.16, 129.7, 129.2, 128.9, 127.8, 127.1 (t, J = 2.9 Hz), 125.8,
25.2, 122.52, 122.50, 122.1, 121.8, 120.5 (t, J = 264.7 Hz). IR (film): 3067, 2929,
-1
590, 1491, 1465, 1374, 1250, 1201, 1156, 1134, 1066, 968, 753, 726, 689 cm . MS
+
+
+
(ESI, m/z): 322.1 (M+H ). HRMS (ESI): Calcd. for C H F NO (M+H ): 322.1038,
2
0
14 2
found: 322.1040.
General Procedures for the Preparation of Compounds 6b-6k (Table 4). To
an oven-dried 10 mL Schlenk Tube A was added t-BuOK (107.7 mg, 0.96 mmol) in
glove box and then the flask was moved out of the glove box. Under argon
atmosphere, DMF (0.3 mL) was injected and the reaction mixture was stirred. ArOH
(5b-k) (0.72 mmol) was dissolved in DMF (0.9 mL) and was added dropwise into the
reaction system. The resulting reaction mixture was stirred at room temperature for 30
min and was left to be used.
To another oven-dried 10 mL Schlenk Tube
-(difluoro(phenylsulfonyl)methyl)phenanthridine (1a) (73.9 mg, 0.2 mmol, 1.0 equiv)
and then the flask was evacuated and backfilled with pure argon for 3 times. PhCHO
21.2 mg, 0.2 mmol, 1.0 equiv) mixed with DMF (1.0 mL) was added via syringe in
one portion and the reaction mixture was stirred. Next, 1.0 mL of the reaction mixture
containing ArOK (0.53 mmol, 2.7 equiv) and t-BuOK (0.18 mmol, 0.9 equiv)] was
B
was added
6
(
[
taken out from the Schlenk Tube A and was added dropwise into the reaction system
of Schlenk Tube B. Then, the resulting reaction mixture was stirred at room
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6
temperature and room light illumination under argon atmosphere for 12 h. After the
reaction was complete, the mixture was quenched with H O (5 mL). The aqueous
2
layer was extracted with EtOAc (8 mL × 3) and the combined organic layer was dried
over anhydrous MgSO . After the solution was filtered, the solvent was evaporated
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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7
8
9
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1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
under reduced pressure and the residue was mixed with silica gel and purified by
column chromatography on silica gel by using PE/EtOAc (80:1, v/v) as eluent to
provide compounds 6b-6k.
6
-((4-(tert-Butyl)phenoxy)difluoromethyl)phenanthridine (6b) (Table 4) Pale
o
1
yellow solid (37.9 mg, 56%). M.p. 103 105 C. H NMR (400 MHz, CDCl ) : δ 8.68
3
(t, J = 9.8 Hz, 2H), 8.58 (d, J = 8.0 Hz, 1H), 8.34 (d, J = 8.0 Hz, 1H), 7.90 – 7.86 (m,
1
H), 7.81 – 7.73 (m, 3H), 7.42 (d, J = 8.8 Hz, 2H), 7.37 (d, J = 8.8 Hz, 2H), 1.34
1
9
13
1
(
s,9H). F NMR (376 MHz, CDCl ) : δ 68.0 (s, 2F). C{ H} NMR (100 MHz,
3
CDCl ) : δ 149.5 (t, J = 31.4 Hz), 148.7, 148.2 (t, J = 1.8 Hz), 142.0, 134.2, 131.2,
3
131.1, 129.2, 128.8, 127.7, 127.2 (t, J = 2.9 Hz), 126.5, 125.1, 122.49, 122.45, 122.1,
121.2, 120.4 (t, J = 265.0 Hz), 34.6, 31.5. IR (film): 3080, 2963, 2906, 1619, 1510,
1465, 1446, 1373, 1332, 1250, 1209, 1173, 1137, 1103, 1067, 1017, 968, 856, 788,
-1
+
762, 727, 559 cm . MS (ESI, m/z): 378.1 (M+H ). HRMS (ESI): Calcd. for
+
+
C H F NO (M+H ): 378.1664, found: 378.1662.
24
22 2
6
-(Difluoro(4-(2-methoxyethyl)phenoxy)methyl)phenanthridine (6c) (Table
1
4
8
7
3
) Yellow oil (48.0 mg, 63%). H NMR (400 MHz, CDCl ) : δ 8.70 – 8.67 (m, 2H),
3
.61 – 8.59 (m, 1H), 8.34 – 8.31 (m, 1H), 7.92 – 7.88 (m, 1H), 7.82 – 7.74 (m, 3H),
.34 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 3.60 (t, J = 7.0 Hz, 2H), 3.36 (s,
1
9
13
1
H), 2.88 (t, J = 7.0 Hz, 2H). F NMR (376 MHz, CDCl ) : δ 67.9 (s, 2F). C{ H}
3
NMR (100 MHz, CDCl ) : δ 149.4 (t, J = 31.6 Hz), 148.9, 142.0, 136.7, 134.1, 131.12,
3
1
1
1
8
31.09, 130.0, 129.2, 128.8, 127.7, 127.1 (t, J = 2.8 Hz), 125.1, 122.4, 122.1, 121.7,
20.4 (t, J = 264.8 Hz), 73.5, 58.8, 35.6. IR (film): 3067, 3028, 2925, 2870, 1612,
573, 1532, 1508, 1465, 1446, 1374, 1333, 1307, 1250, 1204, 1156, 1067, 1019, 967,
-1
+
52, 762, 727 cm . MS (ESI, m/z): 380.1 (M+H ). HRMS (ESI): Calcd. for
+
+
C H F NO (M+H ): 380.1457, found: 380.1455.
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6
-(Difluoro(p-tolyloxy)methyl)phenanthridine (6d) (Table 4) White solid
o
1
(
44.2 mg, 66%). M.p. 88 90 C. H NMR (400 MHz, CDCl ) : δ 8.69 (dd, J = 8.4
3
Hz, 0.8Hz, 1H), 8.65 (d, J = 8.4 Hz, 1H), 8.56 (d, J = 8.0 Hz, 1H), 8.33 (dd, J = 8.0
Hz, 1.2 Hz, 1H), 7.89 – 7.85 (m, 1H), 7.81 – 7.71 (m, 3H), 7.32 (d, J = 8.4 Hz, 2H),
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
19
7
.18 (d, J = 8.4 Hz, 2H), 2.34 (s, 3H). F NMR (376 MHz, CDCl ) : δ 67.8 (s, 2F).
3
13
1
C{ H} NMR (100 MHz, CDCl ) : δ 149.5 (t, J = 31.5 Hz), 148.3, 142.0, 135.5,
3
1
1
1
7
34.1, 131.14, 131.07, 130.1, 129.2, 128.8, 127.7, 127.1 (t, J = 2.9 Hz), 125.1, 122.46,
22.44, 122.1, 121.7, 120.4 (t, J = 264.3 Hz), 20.9. IR (film): 3076, 3050, 2924, 1617,
573, 1507, 1465, 1446, 1374, 1333, 1307, 1250, 1203, 1169, 1134, 1066, 967, 819,
-1
+
58, 724, 555 cm . MS (ESI, m/z): 336.1 (M+H ). HRMS (ESI): Calcd. for
+
+
C H F NO (M+H ): 336.1194, found: 336.1192.
21
16 2
6
-(Difluoro(m-tolyloxy)methyl)phenanthridine (6e) (Table 4) Yellow oil
1
(
42.9 mg, 64%). H NMR (400 MHz, CDCl ) : δ 8.67 – 8.62 (m, 2H), 8.54 (d, J = 8.0
3
Hz, 1H), 8.31 (dd, J = 8.0, 1.2 Hz, 1H), 7.85 (t, J = 7.6 Hz, 1H), 7.78 – 7.69 (m, 3H),
1
9
7.29 – 7.21 (m, 3H), 7.04 – 7.02 (m, 1H), 2.36 (s, 3H). F NMR (376 MHz, CDCl ) :
3
13
1
δ 67.8 (s, 2F). C{ H} NMR (100 MHz, CDCl ) : δ 150.5 (t, J = 1.7 Hz), 149.4 (t, J
3
= 31.4 Hz), 142.0, 139.8, 134.1, 131.10, 131.06, 129.3, 129.1, 128.8, 127.7, 127.1 (t,
J = 2.9 Hz), 126.6, 125.1, 122.44, 122.42, 122.07 , 120.4 (t, J = 265.1 Hz), 118.7,
2
1
1.5. IR (film): 3080, 2915, 1612, 1587, 1529, 1488, 1464, 1446, 1373, 1333, 1252,
-1
+
187, 1157, 1066, 970, 762, 730, 687 cm . MS (ESI, m/z): 336.1 (M+H ). HRMS
+
+
(
ESI): Calcd. for C H F NO (M+H ): 336.1194, found: 336.1195.
21 16 2
6
-(Difluoro(o-tolyloxy)methyl)phenanthridine (6f) (Table 4) White solid
o
1
(
44.1 mg, 66%). M.p. 103 105 C. H NMR (400 MHz, CDCl ) : δ 8.69 (d, J = 8.4
3
Hz, 1H), 8.65 (d, J = 8.4 Hz, 1H), 8.56 (d, J = 8.0 Hz, 1H), 8.32 (d, J = 8.8 Hz, 1H),
7
.86 (t, J = 7.8 Hz, 1H), 7.79 – 7.70 (m, 3H), 7.55 (d, J = 8.0 Hz, 1H), 7.22 (t, J = 7.8
19
Hz, 2H), 7.13 (t, J = 7.4 Hz, 1H), 2.32 (s, 3H). F NMR (376 MHz, CDCl ) : δ 67.2
3
13
1
(
s, 2F). C{ H} NMR (100 MHz, CDCl ) : δ 149.6 (t, J = 31.9 Hz), 149.2, 142.1,
3
1
1
3
34.2, 131.5, 131.2, 131.1, 131.0, 129.2, 128.8, 127.7, 127.2 (t, J = 3.3 Hz), 126.9,
25.6, 125.1, 122.49, 122.47, 122.1, 121.5, 120.7 (t, J = 265.2 Hz), 16.9. IR (film):
080, 2963, 2933, 1614, 1588, 1528, 1493, 1465, 1446, 1374, 1333, 1307, 1250, 1221,
29
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