Hypervalent Iodine/HF Reagents for the Synthesis of 3-Fluoropyrrolidines

Article abstract of DOI:10.1021/acs.joc.7b01266

The intramolecular aminofluorination of homoallylamine derivatives using a reagent system of PhI(OAc)₂ and Py·HF in CH₂Cl₂ at room temperature for 5 h gave N-tosyl-3-fluoropyrrolidines in good to high yields. Furthermore, the catalytic aminofluorination was furnished by the reaction using p-iodotoluene as a catalyst in the presence of Py·HF as a fluorine source and mCPBA as a terminal oxidant.

Full text of DOI:10.1021/acs.joc.7b01266

Article
pubs.acs.org/joc
Hypervalent Iodine/HF Reagents for the Synthesis of
3‑Fluoropyrrolidines
Tsugio Kitamura,* Azusa Miyake, Kensuke Muta, and and Juzo Oyamada
Department of Chemistry and Applied Chemistry, Graduate School of Science and Engineering, Saga University, Honjo-machi, Saga
840-8502, Japan
S
* Supporting Information
ABSTRACT: The intramolecular aminofluorination of homoallylamine
derivatives using a reagent system of PhI(OAc)2 and Py·HF in CH2Cl2 at
room temperature for 5 h gave N-tosyl-3-fluoropyrrolidines in good to high
yields. Furthermore, the catalytic aminofluorination was furnished by the
reaction using p-iodotoluene as a catalyst in the presence of Py·HF as a
fluorine source and mCPBA as a terminal oxidant.
Scheme 1. Intramolecular Aminofluorination Giving 3-
Fluoropyrrolidines
INTRODUCTION
■
3-Fluoropyrrolidine derivatives are biologically active com-
pounds and have attracted much attention as dipeptidyl
peptidase (DPP) IV inhibitors (Figure 1),1 together with
other activities, such as glucokinase activators,2 prolyl
oligopeptidase inhibitors,3 and purine nucleoside phosphorylase
inhibitors.4
Figure 1. Examples of DPP IV inhibitors bearing 3-fluoropyrrolidine
units.
The representative synthetic approach to the 3-fluoropyrro-
lidines has been performed by fluorination of 3-hydroxylpyrro-
lidines5 and pyrrolidines.6 Although a few reviews on
aminofluorination of alkenes have been reported recently,7
intramolecular aminofluorination is a direct and convenient
reaction introducing a fluorine atom to nitrogen-containing
heterocycles, which is a highly efficient method for performing
the ring-construction and the introduction of fluorine atom at
the same time. However, there are few reactions which have
reported generation of 3-fluoropyrrolidines until now, and the
substrate and the reagent are restricted as shown in Scheme 1.
It was reported that intramolecular aminofluorination of
homoallylamines activated by silyl groups proceeded in the
presence of Selectfluor as a fluorinating agent to give 3-
fluoropyrrolidines (eq 1 in Scheme 1).8 This method needs
activation by a silyl group, and significant generation of the
byproduct by fluorodesilylation cannot be avoided. Pd-
catalyzed intramolecular oxidative aminofluorination of styrene
derivatives was achieved using N-fluorobenzenesulfonimide
(NFSI) as a fluorinating agent to give 3-fluoropyrrolidines (eq
2 in Scheme 1).9 The diastereoselectivity of the product was
low and this reaction could not be applied to an aliphatic
homoallylamine. It was also reported that hypervalent iodine-
mediated intramolecular aminofluorination of homoallylamines
provided 3-fluoropyrrolidines in the presence of BF3·OEt2 (eq
3 in Scheme 1).10 In this article, BF3·OEt2 was used as a
fluorine source as well as an activating agent of PhIO. However,
PhIO is not suitable for long-term preservation, and it may be
difficult to use BF3·OEt2 as the fluorine source in the catalytic
Special Issue: Hypervalent Iodine Reagents
Received: May 23, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.7b01266
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Article
aminofluorination reaction because BF3·OEt2 reacts with a
terminal oxidant or other reagents.
we have adopted the more economical PhI(OAc)2 for this
study. Increasing the amount of Py·HF reagent maintained the
yield of 2a (entry 9), and a slight increment of PhI(OAc)2
increased the yield to 94% (entry 10). However, further
increase of PhI(OAc)2 did not improve the yield (entry 11).
Therefore, we adopted the condition of entry 10 as an optimal
condition.
With the optimized conditions in hand, we next examined
the scope of the substrate using PhI(OAc)2 (condition A) or
PhI(OCOCF3)2 (condition B). The results are given in Table
2. Under the condition A, homoallylamines 1b and 1c
Although hypervalent iodine compounds have been widely
used in organic synthesis as low toxic, mild, and environ-
mentally benign reagents,11 the metal-free hypervalent iodine-
mediated five-membered ring formation reactions are few.
Considering the viewpoint of the high biological activity of
pyrrolidines, a simpler and more efficient synthetic method
should be developed as a challenging subject. Thus, we
envisaged that a fluorinating reagent composed of a hypervalent
iodine and HF12 would be effective for synthesis of 3-
fluoropyrrolidines by intramolecular aminofluorination of
homoallylamines. In this reagent system, PhI(OAc)2 can be
used as a stable hypervalent iodine reagent. More importantly,
this reagent system can be extended to a catalytic intra-
molecular aminofluorination reaction. In this article, we report
the hypervalent iodine-mediated intramolecular aminofluorina-
tion reactions giving 3-fluoropyrrolidines, which cover from a
stoichiometric aminofluorination reaction using a stable
PhI(OAc)2 to a catalytic aminofluorination with an iodoarene
catalyst.
a
Table 2. Aminofluorination of Homoallylamine Derivatives
RESULTS AND DISCUSSION
■
First, we chose N-tosyl-3-butenylamine (1a) as a model
substrate, PhI(OAc)2 as a hypervalent iodine reagent, and
pyridine·HF complex (Py·HF) as a fluorine source. When the
fluorination of 1a was conducted using the Py·HF reagent in
the presence of PhI(OAc)2 in CH2Cl2 at room temperature for
5 h, N-tosyl-3-fluoropyrrolidine (2a) was obtained in 75% yield
(Table 1, entry 1). Instead of the Py·HF reagent, hydrofluoric
a
Table 1. Optimization of Fluorination Reactions of 1a
b
entry
iodine reagent (equiv)
HF reagent (HF equiv)
yield (%)
1
PhI(OAc)2 (1.2)
PhI(OAc)2 (1.2)
PhI(OAc)2 (1.2)
PhI(OAc)2 (1.2)
PhIO (1.2)
Py·HF (25)
55% HF (25)
Et3N·5HF (25)
Et3N·3HF (25)
Py·HF (25)
Py·HF (25)
Py·HF (25)
Py·HF (25)
Py·HF (10)
Py·HF (10)
Py·HF (10)
75
52
38
trace
76
76
82
16
76
94
76
2
3
4
5
6
PhI(OCOCF3)2 (1.2)
PhI(OPiv)2 (1.2)
PhI(OH)OTs (1.2)
PhI(OAc)2 (1.2)
PhI(OAc)2 (1.35)
PhI(OAc)2 (1.5)
7
8
9
10
11
a
Condition A: 1 (0.4 mmol), PhI(OAc)2 (0.54 mmol), Py·HF (4
a
mmol HF), and CH2Cl2 (1 mL), rt, 5 h. Condition B: PhI(OCOCF3)2
Conditions: 1a (0.2 mmol), an iodine reagent, a HF reagent, CH2Cl2
b
b
(0.5 mL), rt, 5 h. Determined by 19F NMR.
(0.54 mmol) was used instead of PhI(OAc)2. Yields were determined
by 19F NMR. Values in parentheses represent the cis:trans ratio.
acid (55% HF), trietylamine pentahydrofluoride (TEA·5HF)
and triethylamine trihydrofluoride (TEA·3HF) were examined
as the fluorine source but the yield was not improved (entries
2−4). Screening the hypervalent iodine reagents, almost the
same results as the case of PhI(OAc)2 were obtained in the
cases of PhIO and PhI(OCOCF3)2, respectively (entries 5 and
6). The reaction using PhI(OPiv)2 gave the improved yield
(82%) of 2a (entry 7), but the use of Koser’s salt
(PhI(OH)OTs) resulted in a low yield (entry 8). Although
PhI(OPiv)2 was stable and prepared readily from PhI(OAc)2,
protected with mesyl (Ms) and nosyl (Ns) groups gave the
corresponding N-mesyl- and N-nosyl-3-fluoropyrrolidines (2b
and 2c) in 67 and 85% yields, respectively (entries 1 and 2).
The similar reaction of N-tosyl-2-phenyl-3-butenylamine (1d)
under the condition A afforded N-tosyl-4-fluoro-2-phenyl-
pyrrolidine (2d) in 63% yield (entry 3). However, the
purification by column chromatography on silica gel resulted
in a large loss of the product due to the contamination of AcO-
incorporated byproducts. When the reaction of 1d was
conducted under the condition B, the product 2d was isolated
B
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in 69% yield (entry 4). The same situation was observed in the
cases of the substrates 1e−1h substituted with o-tolyl, p-tolyl,
ethyl, or isopropyl groups at the 2 position. 2-Substituted 4-
fluoropyrrolidines 2d−2h were obtained in 50−70% yields
(entries 5−12). Interestingly, sterically unfavorable cis-isomers
were selectively formed, showing that the cis:trans ratio was in
the range from 65:35 to 80:20. N-Tosyl-3-methyl-3-butenyl-
amine (1i) also underwent the aminofluorination reaction to
afford N-tosyl-3-fluoro-3-methylpyrrolidine (2i) in 86% yield
(entry 13).
Scheme 4. Possible Mechanism for Intramolecular
Aminofluorination
To compare with other reagent systems, we examined the
aminofluorination of N-tosyl-4-pentenylamine (3) using the
reagent system of PhI(OCOCF3)2 and Py·HF. As shown in
Scheme 2, six-membered N-tosyl-3-fluoropiperidine (4) was
obtained in 69% yield. The present reagent system provides the
same result as the previously reported reagents.13
Scheme 2. Aminofluorination of N-Tosyl-4-pentenylamine 3
To obtain the information about the reaction mechanism for
the intramolecular aminofluorination, we examined the
competitive reaction between homoallylamines 1a and 1i. An
equimolar mixture of 1a and 1i was subject to undergo the
aminofluorination reaction (Scheme 3). As expected, only the
favored trans isomer of 6 or the neighboring group participation
of the tosyl group in the cation 8.
To extend the scope of substrates and get more information
about the mechanism, we further studied the fluorocyclization
of homoallylalcohols 9 and 3-butenoic acid (10), as shown in
Scheme 5. The fluorination reaction of homoallylalcohols 9 was
Scheme 3. Competitive Fluorination
Scheme 5. Fluorocyclization of 9 and 11
reaction of 1i occurred preferentially and 3-fluoro-3-methyl-
pyrrolidine 2i was obtained in 75% yield. This result indicates
that a hypervalent iodine reagent selectively reacts with the
more electron-rich olefinic moiety of 1i than that of 1a.
The present intramolecular aminofluorination reaction may
proceed by the mechanism shown in Scheme 4. In the
mechanism via bridged iodonium intermediate 5,12f,14 difluor-
oiodobenzene formed in situ is activated by HF and then
attacks the double bond of homoallylamines 1 to generate
bridged iodonium salts 5. Attacking the terminal carbon by the
nucleophilic nitrogen atom, the bridged iodonium salts 5
undergo the ring-opening to afford five-membered pyrrolidines
6, which are subject to SN 2-type substitution by fluoride ion.
Finally, 3-fluoropyrrolidines 2 are formed by deprotonation.
However, we could not discard another mechanism via an
aminofluoroiodonium intermediate.7a,13a,b In this mechanism,
the difluoroidobenzene reacts at the tosylamio group to
generate the aminofluoroiodonium intermediate 7. Then, the
intermediate 7 reacts with the double bond to generate
carbocation 8, which is attacked by fluoride ion to give 2. If the
rate-determining step is the intramolecular cyclization of 7 to 8,
the high reactivity of 1i satisfies with the result of the
competitive reaction. The preferential formation of the cis
isomer of 2 in the case of 2-substituted homoallylamines 1d-1i
may be explained by the preferential formation of the sterically
conducted using the reagent system of PhI(OPiv)2 and Py·HF
in CH2Cl2. As expected, fluorinated tetrahydrofuran derivatives
11 were obtained in 54−65% yields as a mixture of cis and trans
isomers. Similarly, butenoic acid 10 underwent the fluorocyc-
lization to give fluorinated butyrolactone 12 in 45% yield.
These results are consistent with those from the reaction with
(difluoroiodo)toluene,15 suggesting that the oxygen part acts as
the nucleophilic site in the fluorocyclization process. Namely,
the behavior of 9 and 10 is similar to that of homoallylamines 1.
Consequently, these results support the mechanism via bridged
iodonium intermediates 5 and also improve the usefulness of
this method.
The catalytic use of reagents is one of significant reactions
with respect to the guiding principle of Green Chemistry.16 In
the stoichiometric aminofluorination of homoallylamines 1
using the PhI(OAc)2/Py·HF reagent, iodobenzene is produced
as the byproduct. If the generated iodobenzene would be
reoxidized to iodosylbenzene, the iodosylbenzene could be
converted into difluoroiodobenzene and participate again into
the aminofluorination reaction. Thus, we examined the catalytic
C
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aminofluorination of homoallylamines using iodoarene cata-
lysts.
Table 4. Scope of Substrates for Catalytic
Aminofluorination
a
First, we studied the aminofluorination reaction of 1a using
p-iodotoluene (20 mol%) as a catalyst in the presence of Py·HF
(10 equiv of HF) as a fluorine source and mCPBA (2 equiv) as
a terminal oxidant. The results are given in Table 3. The
Table 3. Catalytic Aminofluorination of Homoallylamines
1aa
Py·HF (equiv of
mCPBA
(equiv)
time
(h)
yield
b
entry
ArI
HF)
(%)
1
2
3
4
5
6
7
8
9
p-TolI
p-TolI
p-TolI
p-TolI
PhI
10
15
20
25
20
20
20
20
20
2
2
2
2
2
2
2
2
2
8
8
8
8
8
8
8
8
8
50
63
82
71
54
59
42
48
46
o-TolI
o-AnI
p-AnI
2,6-
(MeO)2C6H3I
2,4,6-Me3C6H2I
p-TolI
a
Conditions: 1 (0.4 mmol), ArI (0.08 mmol), Py·HF (HF, 8 mmol),
mCPBA (0.4 mmol), CH2Cl2 (1 mL), rt, 2 h.
10
11
20
20
2
1
8
2
52
74
homoallylamine 1 (0.4 mmol) and CH2Cl2 (0.5 mL) were added, and
the mixture was stirred for 5 h at room temperature. After completion
of the reaction, the yield of product 2 was determined by 19F NMR
using fluorobenzene as an internal standard. The reaction mixture was
neutralized with aqueous NaHCO3 and extracted with CH2Cl2 (10 mL
× 3). The organic phase was dried over anhydrous Na2SO4 and
concentrated by a Rotary evaporator. The product 2 was purified by
column chromatography on silica gel with hexane/EtOAc (70:30).
Condition B. The fluorination reaction of 1 was carried out in the
same procedure as the condition A except for using PhI(OCOCF3)2
(232 mg, 0.54 mmol) instead of PhI(OAc)2.
a
Conditions: 1a (0.2 mmol), ArI (0.04 mmol), Py·HF, mCPBA,
b
CH2Cl2 (0.5 mL), rt. Yield was determined by 19F NMR.
reaction of 1a in CH2Cl2 at room temperature for 8 h gave 3-
fluoropyrrolidine 2a in 50% yield (entry 1). Increasing the
amount of Py·HF (entries 2−4), the reaction using 4 equiv of
HF gave the highest yield (82%) of 2a (entry 3). Although we
screened other iodoarenes (entries 5−10), the yield of 2a was
not improved. Even though the amount of mCPBA was
decreased to 1 equiv, the product was obtained in a reasonable
yield (74%) (entry 11). Accordingly, we further examined the
scope of the substrate using the conditions of entry 11, Table 3.
We examined several homoallylamines 1 for catalytic
aminofluorination using p-iodotoluene. The results are given
in Table 4. The substrates 1 employed in the catalytic
aminofluorination afforded products 2 in good to high yields.
This indicates that the aminofluorination of 1 also proceeds
catalytically.
3-Fluoro-1-[(4-methylphenyl)sulfonyl]pyrrolidine (2a).10 Under
the condition A using 0.2 mmol of 1a (Table 1, entry 10), the
product was isolated by column chromatography to give 37.5 mg
1
(77%) of 2a as colorless solid, mp 101.3−103.9 °C. H NMR (400
MHz, CDCl3): δ = 1.86−2.01 (m, 1H), 2.08−2.18 (m, 1H), 2.43 (s,
3H), 3.24−3.30 (m, 1H), 3.48−3.57 (m, 3H), 5.14 (d, J = 52 Hz, 1H),
7.33 (d, J = 8 Hz, 2H), 7.72 (d, J = 8 Hz, 2H). 13C{1H} NMR (100
MHz, CDCl3): δ = 21.5, 32.5 (d, J = 22 Hz), 45.8, 54.3 (d, J = 23 Hz),
92.2 (d, J = 177 Hz), 127.5, 129.7, 133.6, 143.6. 19F NMR (376 MHz,
CDCl3): δ = −175.8.
3-Fluoro-1-(methylsulfonyl)pyrrolidine (2b). Under the condition
A (Table 2, entry 1), the product was isolated by column
chromatography to give 42.1 mg (63%) of 2b as colorless solid, mp
CONCLUSION
■
1
In summary, we have demonstrated that hypervalent iodine-
mediated intramolecular aminofluorination of homoallylamine
derivatives 1 proceeds efficiently to give 3-fluoropyrrolidine
derivatives 2. This reaction takes place both with a
stoichiometric PhI(OAc)2/Py·HF reagent and with a catalytic
amount of p-iodotoluene, and provides an efficient method for
synthesis of 3-fluoropyrolidine derivatives. The present method
is applied to fluorocyclization of the substrates with oxygen
nucleophiles, such as homoallylalcohols 9 and butenoic acid 10.
102.4−103.6 °C. H NMR (400 MHz, CDCl3): δ = 1.99−2.19 (m,
1H), 2.29−2.39 (m, 1H), 2.86 (s, 3H), 3.38−3.69 (m, 4H), 5.27 (d, J
= 52 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ = 33.1 (d, J = 22
Hz), 34.7, 46.2, 54.9 (d, J = 23 Hz), 92.9 (d, J = 177 Hz). 19F NMR
(376 MHz, CDCl3): δ = −176.8. HRMS (EI-EB): m/z [M]+ calcd for
C5H10FNO2S: 167.0416; found: 167.0415.
3-Fluoro1-[(2-nitrophenyl)sulfonyl]pyrrolidine (2c). Under the
condition A (Table 2, entry 2), the product was isolated by column
1
chromatography to give 93.3 mg (85%) of 2c as yellow oil. H NMR
(400 MHz, CDCl3): δ = 1.97−2.18 (m, 1H), 2.30−2.32 (m, 1H),
3.52−3.83 (m, 4H), 5.26 (d, J = 52 Hz, 1H), 7.63 (d, J = 7.2 Hz, 1H),
7.72−7.69 (m, 2H), 8.01 (d, J = 6 Hz, 1H). 13C{1H} NMR (100 MHz,
CDCl3): δ = 32.6 (d, J = 22 Hz), 45.9, 54.2 (d, J = 24 Hz), 92.1 (d, J =
178 Hz), 123.96, 124.0, 130.3, 131.7, 133.7,148.2. 19F NMR (376
MHz, CDCl3): δ = −177.0. HRMS (EI-EB): m/z [M]+ calcd for
C10H11FN2O4S: 274.0424; found: 274.0424.
EXPERIMENTAL SECTION
■
General Procedure for Fluorination of Homoallylamines 1
with PhI(OAc)2/Py·HF Reagent: Condition A. To a Teflon test
tube were placed PhI(OAc)2 (174 mg, 0.54 mmol), Py·HF reagent
(115 mg, 4 mmol), and CH2Cl2 (0.5 mL). After stirring for 15 min,
D
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4-Fluoro-2-phenyl-1-[(4-methylphenyl)sulfonyl]pyrrolidine
(2d).10 Under the condition B (Table 2, entry 4), the product was
isolated by column chromatography to give 88.2 mg (69%) of 2d as a
mixture of cis and trans isomers, colorless solid, mp 103.9−106.4 °C.
1H NMR (400 MHz, CDCl3): δ = 2.18−2.26 (m, 1H), 2.37 (s, 3H),
3.54−3.65 (m, 1H), 3.80−3.89 (m, 1H), 4.88−4.91 (m, 1H), 5.11 (d, J
= 53 Hz, 1H), 7.18−7.94 (m, 7H), 7.59 (d, J = 8 Hz, 2H). 13C{1H}
NMR (100 MHz, CDCl3): δ = 21.5, 41.5 (d, J = 21 Hz), 55.4 (d, J =
24 Hz), 62.2, 92.0 (d, J = 180 Hz), 126.6, 127.2, 127.5, 128.2, 129.6,
134.5, 141.8, 143.7. 19F NMR (376 MHz, CDCl3): δ = −172.5,
−177.7.
3-Fluoro-1-[(4-methylphenyl)sulfonyl]pyperidine (4).17 Under the
condition B (Scheme 2), the product was isolated by column
chromatography to give 71.0 mg (69%) of 4 as colorless solid, mp
93.4−95.1 °C. 1H NMR (400 MHz, CDCl3): δ = 1.57−1.67 (m, 2H),
1.77−1.87 (m, 2H), 2.44 (s, 3H), 2.86−2.90 (m, 1H), 2.95−3.02 (m,
1H), 3.13−3.15 (m, 1H), 3.35−3.43 (m, 1H), 4.59−4.72 (m, 1H),
7.33 (d, J = 8 Hz, 2H), 7.66 (d, J = 8 Hz, 2H). 13C{1H} NMR (100
MHz, CDCl3): δ = 21.6 (d, J = 6 Hz), 21.9, 29.7 (d, J = 19 Hz), 46.1,
50.0 (d, J = 27 Hz), 86.4 (d, J = 175 Hz), 128.0, 130.1, 133.8, 144.0.
19F NMR (376 MHz, CDCl3): δ = −182.9.
Fluorination of Homoallylalcohols 9 and Butenoic Acid 10. To a
Teflon test tube were placed PhI(OPiv)2 (548.5 mg, 1.35 mmol), Py·
HF reagent (286 mg, 10 mmol), and CH2Cl2 (0.5 mL). After stirring
for 15 min, 9 (1 mmol) and CH2Cl2 (0.5 mL) were added, and the
mixture was stirred for 5 h at room temperature. After completion of
the reaction, the yield of product 11 or 12 was determined by 19F
NMR using fluorobenzene as an internal standard. The reaction
mixture was neutralized with aqueous NaHCO3 and extracted with
CH2Cl2 (10 mL × 3). The organic phase was dried over anhydrous
Na2SO4 and concentrated by a Rotary evaporator. The product was
purified by column chromatography on silica gel with hexane/EtOAc
(70:30). In the case of 3-butenoic acid (10), the reaction of 10 (86.1
mg, 1 mmol) in 1,2-dichloroethane (1 mL) was conducted using Py·
HF reagent (583.5 mg, 20 mmol), PhI(OCOCF3)2 (580.5 mg, 1.35
mmol) at 60 °C for 17 h.
4-Fluoro-2-(2-methylphenyl)-1-[(4-methylphenyl)sulfonyl]-
pyrrolidine (2e). Under the condition B (Table 2, entry 6), the
product was isolated by column chromatography to give 78.7 mg
(59%) of 2e as a mixture of cis and trans isomers, colorless solid, mp
1
160.1−162.6 °C. H NMR (400 MHz, CDCl3): δ = 2.06−2.15 (m,
1H), 2.31−2.48 (m, 7H), 3.59−3.72 (m, 1H), 3.93 (dd, J = 12, 21 Hz,
1H), 5.10−5.22 (m, 2H), 7.09−7.10 (m, 3H), 7.25 (d, J = 8 Hz, 2H),
7.40 (d, J = 6 Hz, 1H), 7.62 (d, J = 8 Hz, 2H). 13C{1H} NMR (100
MHz, CDCl3): δ = 19.4, 21.5, 40.6 (d, J = 20 Hz), 55.4 (d, J = 24 Hz),
59.1, 92.1 (d, J = 180 Hz), 126.0, 126.4, 127.0, 127.5, 129.6, 130.1,
133.54, 134.7, 140.1, 143.7. 19F NMR (376 MHz, CDCl3): δ = −172.6,
−177.8. HRMS (EI-EB): m/z [M]+ calcd for C18H20FNO2S:
333.1199; found: 333.1200.
4-Fluoro-2-(4-methylphenyl)-1-[(4-methylphenyl)sulfonyl]-
pyrrolidine (2f). Under the condition B (Table 2, entry 8), the product
was isolated by column chromatography to give 56.0 mg (42%) of 2f
as a mixture of cis and trans isomers, colorless solid, mp 93.6−95.7 °C.
1H NMR (400 MHz, CDCl3): δ = 1.91−2.55 (m, 8H), 3.54−3.99 (m,
2H), 4.63−4.86 (m, 1H), 5.03−5.20 (m, 1H), 7.08−7.15 (m, 2H),
7.21−7.29 (m, 4H), 7.60−7.65 (m, 2H). 13C{1H} NMR (100 MHz):
δ = 21.0, 21.1, 21.4, 21,5, 41.1 (d, J = 21 Hz), 44.0 (d, J = 21 Hz), 55.4
(d, J = 24 Hz), 56.0 (d, J = 22 Hz), 62.0, 62.3, 91.1 (d, J = 178 Hz),
91.9 (d, J = 180 Hz), 126.3, 126.5, 127.5, 127.7, 128.9, 129.2, 129.3,
129.5, 134.3, 134.6, 136.8, 137.2, 138.4, 138.9, 143.4, 143.6. 19F NMR
(376 MHz, CDCl3): δ = −172.6, −177.6. HRMS (EI-EB): m/z [M]+
calcd for C18H20FNO2S: 333.1199; found: 333.1200.
4-Fluoro-2-phenyltetrahydrofuran (11a). The product 11a (108
mg, 65%) was obtained as a mixture of cis and trans isomers, pale
1
yellow oil. H NMR (400 MHz, CDCl3): δ = 1.85−2.24 (m, 1H),
2.55−2.74 (m, 1H), 3.71−4.39 (m, 2H), 4.88−5.43 (m, 2H), 7.26−
7.38 (m, 5H). 13C{1H} NMR (100 MHz, CDCl3): δ = 41.4 (d, J = 22
Hz), 42.1 (d, J = 21 Hz), 74.0 (d, J = 24 Hz), 74.1 (d, J = 23 Hz), 79.5,
80.4, 94.0 (d, J = 178 Hz), 94.4 (d, J = 176 Hz), 125.7, 126.1, 127.6,
127.7, 128.40, 128.45, 141.2, 141.7. 19F NMR (376 MHz, CDCl3): δ =
−174.1, −171.6. HRMS (EI-EB): m/z [M]+ calcd for C10H11FO:
166.0794; found: 166.9794.
4-Fluoro-2-(2-methylphenyl)tetrahydrofuran (11b). The product
11b (97.3 mg, 54%) was obtained as a mixture of cis and trans isomers,
pale yellow oil. 1H NMR (400 MHz, CDCl3): δ = 1.73−2.10 (m), 2.29
(s), 2.32 (s), 3.76−4.43 (m), 5.03−5.43 (m), 7.11−7.20 (m), 7.42−
7.55 (m). 13C{1H} NMR (100 MHz, CDCl3): δ = 19.0, 19.1, 40.3 (d, J
= 22 Hz), 40.9 (d, J = 21 Hz), 73.7 (d, J = 24 Hz), 73.9 (d, J = 24 Hz),
76.8, 77.5, 94.0 (d, J = 179 Hz), 94.5 (d, J = 176 Hz), 124.4, 125.1,
126.17, 126.21, 127.2, 127.3, 130.0, 130.3, 134.1, 134.6, 139.5, 140.0.
19F NMR (376 MHz, CDCl3): δ = −173.9, −171.3. HRMS (EI-EB):
2-Ethyl-4-fluoro-1-tosylpyrrolidine (2g).10 Under the condition B
(Table 2, entry 10), the product was isolated by column
chromatography to give 65.1 mg (60%) of 2g as a mixture of cis
and trans isomers, yellow viscous oil. 1H NMR (400 MHz, CDCl3): δ
= 0.88−0.95 (m, 3H), 1.62−1.79 (m, 2H), 1.89−2.16 (m, 2H), 2.43
(s, 3H), 3.37−3.50 (m, 1H), 3.61−3.75 (m, 2H), 4.94−5.10 (m, 1H),
7.29−7.33 (m, 2H), 7.70−7.72 (m, 2H). 13C{1H} NMR (100 MHz,
CDCl3): δ = 9.2, 10.6, 21.4, 28.4, 29.0, 36.1 (d, J = 20 Hz), 38.2 (d, J =
22 Hz), 54.6 (d, J = 25 Hz), 55.6 (d, J = 23 Hz), 60.1, 61.4, 91.2 (d, J =
178 Hz), 92.4 (d, J = 179 Hz), 127.4, 127.7, 129.4, 129.7, 134.6, 134.8,
143.4, 143.6. 19F NMR (376 MHz, CDCl3): δ = −171.7, −177.2.
4-Fluoro-2-(1-methylethyl)-1-[(4-methylphenyl)sulfonyl]-
pyrrolidine (2h). Under the condition B (Table 2, entry 12), the
product was isolated by column chromatography to give 47.9 mg
(42%) of 2h as a mixture of cis and trans isomers, colorless solid, mp
m/z [M]+ calcd for C11H13FO: 180.0950; found: 180.0950.
4-Fluorodihydro-2(3H)-furanone (12).15 The product 12 (46.8 mg,
45%) was obtained as pale yellow oil. 1H NMR (400 MHz, CDCl3): δ
= 2.76 (s, 1H), 2.83 (s, 1H), 4.44 (ddd, J = 3, 12, 35 Hz, 1H), 4.58
(dd, J = 12, 24 Hz, 1H), 5.41 (dd, J = 3, 54 Hz, 1H). 13C{1H} NMR
(100 MHz, CDCl3): δ = 35.3 (d, J = 24 Hz), 73.5 (d, J = 26 Hz), 88.5
(d, J = 180 Hz), 173.9. 19F NMR (376 MHz, CDCl3): δ = −176.3.
Representative Procedure for Catalytic Fluorination of
Homoallylamines 1 with p-Iodotoluene/mCPBA/Py·HF Re-
agent. To a Teflon test tube were placed p-iodotoluene (17.4 mg,
0.08 mmol), mCPBA (98.8 mg, 0.4 mmol), Py·HF reagent (229 mg, 8
mmol), and CH2Cl2 (0.5 mL). After stirring for 15 min, homoallyl-
amine 1 (0.4 mmol) and CH2Cl2 (0.5 mL) were added, and the
mixture was stirred for 2 h at room temperature. The reaction mixture
was neutralized with aqueous NaHCO3 and extracted with CH2Cl2
(10 mL × 3). The organic phase was dried over anhydrous Na2SO4
and concentrated by a rotary evaporator. The product 2 was purified
by column chromatography on silica gel with hexane/EtOAc (70:30).
1
87.7−89.9 °C. H NMR (400 MHz, CDCl3): δ = 0.91 (d, J = 8 Hz,
3H), 1.0 (d, J = 8 Hz, 3H), 1.53−1.66 (m, 1H), 1.94−2.14 (m, 1H),
2.43 (s, 3H), 3.49−3.66 (m, 3H), 4.89 (d, J = 55 Hz, 1H), 7.32 (d, J =
8 Hz, 2H), 7.70 (d, J = 8 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3):
δ = 17.6, 20.1, 21.5, 31.3, 33.7 (d, J = 20 Hz), 54.6 (d, J = 26 Hz), 65.6,
91.7 (d, J = 180 Hz), 127.5, 129.8, 134.7, 143.7. 19F NMR (376 MHz,
CDCl3): δ = −171.5, −176.6. HRMS (EI-EB): m/z [M]+ calcd for
C14H20FNO2S: 285.1199; found: 285.1198.
3-Fluoro-3-methyl-1-[(4-methylphenyl)sulfonyl]pyrrolidine (2i).10
Under the condition A (Table 2, entry 13), the product was isolated
by column chromatography to give 88.5 mg (86%) of 2i as colorless
solid, mp 103.2−104.9 °C. 1H NMR (400 MHz, CDCl3): δ = 1.44 (d,
J = 22 Hz, 3H), 1.76−1.93 (m, 1H), 2.04−2.13 (m, 1H), 2.43 (s, 3H),
3.26−3.37 (m, 2H), 3.46−3.58 (m, 2H), 7.33 (d, J = 8 Hz, 2H), 7.71
(d, J = 8 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ = 21.4, 21.7
(d, J = 26 Hz), 37.5 (d, J = 23 Hz), 46.8, 58.2 (d, J = 26 Hz), 100.2 (d,
J = 175 Hz), 127.4, 129.58, 133.4, 143.5. 19F NMR (376 MHz,
CDCl3): δ = −141.2.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b01266.
1H and 13C NMR spectra of products 2, 11, 4, and 12
(PDF)
E
DOI: 10.1021/acs.joc.7b01266
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
K.; Oyamada, J. Synthesis 2015, 47, 3241−3245. (f) Kitamura, T.;
Muta, K.; Oyamada, J. J. Org. Chem. 2015, 80, 10431−10436.
(g) Kitamura, T. Yuki Gosei Kagaku Kyokaishi 2017, 75, 134−143.
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Org. Biomol. Chem. 2012, 10, 8566−8569. (b) Kong, W.; Feige, P.; de
Haro, T.; Nevado, C. Angew. Chem., Int. Ed. 2013, 52, 2469−2473.
(c) Suzuki, S.; Kamo, T.; Fukushi, K.; Hiramatsu, T.; Tokunaga, E.;
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AUTHOR INFORMATION
Corresponding Author
*E-mail: kitamura@cc.saga-u.ac.jp
ORCID
Tsugio Kitamura: 0000-0001-5592-5228
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
This work was supported by JSPS KAKENHI (Grant Number
16K05703).
■
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DOI: 10.1021/acs.joc.7b01266
J. Org. Chem. XXXX, XXX, XXX−XXX