Boron trifluoride etherate functioning as a fluorine source in an iodosobenzene-mediated intramolecular aminofluorination of homoallylic amines

Article abstract of DOI:10.1021/ol500238k

A widely used Lewis acid BF₃·Et₂O was shown to be capable of acting as an efficient fluorinating agent in an intramolecular aminofluorination reaction of homoallylic amines to provide 3-fluoropyrrolidines mediated by a commercially available hypervalent iodine(III) reagent PhIO at room temperature. A mechanism involving a carbocation intermediate was proposed on the basis of several experimental evidence.

Full text of DOI:10.1021/ol500238k

Letter
pubs.acs.org/OrgLett
Boron Trifluoride Etherate Functioning as a Fluorine Source in an
Iodosobenzene-Mediated Intramolecular Aminofluorination of
Homoallylic Amines
Jian Cui, Qun Jia, Ruo-Zhu Feng, Shan-Shan Liu, Tian He, and Chi Zhang*
State Key Laboratory of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering
(Tianjin), The Research Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, P. R. of China
S
* Supporting Information
ABSTRACT: A widely used Lewis acid BF3·Et2O was shown to be capable of acting
as an efficient fluorinating agent in an intramolecular aminofluorination reaction of
homoallylic amines to provide 3-fluoropyrrolidines mediated by a commercially
available hypervalent iodine(III) reagent PhIO at room temperature. A mechanism
involving a carbocation intermediate was proposed on the basis of several
experimental evidence.
he introduction of a fluorine atom into organic molecules
from the competing dehydration reaction and rearrangement
processes.5b,c,6 There is another strategy to synthesize 3-
fluoropyrrolidine via a heteroannulation reaction of acyclic
alkene having an amino functionality, which has, however,
received much less attention. The only example following this
strategy, with homoallylic amines containing a silyl group as
substrates, was reported by Gouverneur et al. in which
Selectfluor was employed as the fluorine source compound;
however, the yield of silicon-containing 3-fluoropyrrolidines
was not satisfactory.7 It is worth noting that the same
heteroannulation strategy has been successfully applied in the
synthesis of other important heterocycles including 3-
fluoropiperidine,8a−d fluorinated spiro-fused oxazoline,8e and
fluorinated tetrahydrofuroindole8f in recent years.
T
can greatly change their physical, chemical, and biological
properties,1 which may explain why ca. 40% of agrochemicals
and ca. 20% of pharmaceuticals contain at least one fluorine
atom.2 3-Fluoropyrrolidine, a fluorine-containing five-mem-
bered heterocycle, is the key structural unit presenting in the
inhibitors of many enzymes (Figure 1, I and II), which are
In fluorination reactions, the choice of fluorine source
compounds is the key issue. The last four decades saw the
emergence of mild organic fluorinating agents such as DAST
and its derivatives,5f,6 N-fluorobenzenesulfonimide (NFSI),9
Selectfluor,10 and PhenoFluor,11 which have been successfully
used in deoxyfluorination,6,11 electrophilic fluorination,9,10,12
radical fluorination,13 and transition-metal-catalyzed fluorina-
tion reaction.12c,14 Compared with traditional fluorinating
agents including molecular fluorine, sulfur tetrafluoride, these
organo-fluorinating agents were relatively stable and easily
handled, which resulted in their broad application in
fluorination reactions; however, there are still some issues
needed to be addressed. For example, DAST, Selectfluor, and
NFSI are expensive and show poor atom economy in
fluorination reactions. DAST is also sensitive to moisture.
Our goal is to develop an efficient and operationally simple
aminofluorination reaction in which a readily available, cheap,
and easily handled fluorine source compound is employed. It
Figure 1. Selected biologically active compounds containing the 3-
fluoropyrrolidine moiety.
implicated in several diseases including diabetes, cancer, and
mood disorders.3 Some of the molecules bearing a 3-
fluoropyrrolidine moiety show good antibacterial activity
exemplified as compound III (Figure 1).4 Usually, the synthesis
of 3-fluoropyrrolidine relies on the deoxyfluorination of 3-
hydroxypyrrolidine using diethylaminosulfur trifluoride
(DAST) or its derivatives,5 but such a method often suffers
Received: January 22, 2014
Published: February 26, 2014
© 2014 American Chemical Society
1442
dx.doi.org/10.1021/ol500238k | Org. Lett. 2014, 16, 1442−1445

Organic Letters
Letter
was reported that BF3·Et2O, a widely used Lewis acid, could act
as the fluorine source in the epoxide ring-opening reaction,15
Prins reaction,16 and carbofluorination reaction.17 In addition,
BF3·Et2O together with toxic Pb(OAc)4 could also realize
aromatic fluorination reaction.18 Herein, as part of our
continuing research on the new synthetic applications of a
commercially available hypervalent iodine(III) reagent iodoso-
benzene (PhIO),19 we first disclosed a metal-free oxidative
transformation to provide 3-fluoropyrrolidines with BF3·Et2O
as the fluorine source and PhIO as the oxidant.
Table 2. Substrate Scope of Intramolecular
Aminofluorination Reaction Using BF3·Et2O as the Fluorine
a
Source
At the beginning of the reaction, the model substrate N-(but-
3-en-1-yl)-4-methylbenzenesulfonamide (1a) was treated with
2.0 equiv of PhIO and 4.0 equiv of BF3·Et2O in dichloro-
methane at room temperature. After 2.5 h, it was found that the
desired cyclic product 2a could be obtained in 81% yield along
with a trace amount of hydroxylated product 3a being formed
(Table 1, entry 1). When BF3·Et2O was replaced by other
a
Table 1. Optimization of the Reaction Conditions
b
yield (%)
entry fluorine source (equiv)
solvent
time (h)
2a
3a
1
BF3·Et2O (4.0)
AlF3 (4.0)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
1,4-dioxane
EtOAc
2.5
24
24
24
24
24
4
81
0
5
0
c
2
d
d
c
3
4
FeF3 (4.0)
0
0
CsF (4.0)
0
0
5
6
SbF3 (4.0)
0
0
e
AgF (4.0)
0
0
7
BF3·THF (4.0)
BF3·Et2O (4.0)
BF3·Et2O (4.0)
BF3·Et2O (4.0)
BF3·Et2O (4.0)
BF3·Et2O (4.0)
BF3·Et2O (4.0)
BF3·Et2O (4.0)
BF3·Et2O (4.0)
BF3·Et2O (3.0)
BF3·Et2O (2.0)
BF3·Et2O (1.0)
BF3·Et2O (0.5)
BF3·Et2O (1.0)
71
22
30
0
10
8
8
4
f
9
0.25
2
18
0
g
10
CH3CN
n-PrOH
HFIP
h
11
12
24
2
0
0
45
8
8
i
13
14
CH3COOH
ClCH2CH2Cl
CHCl3
2
0
1.5
12
3
72
58
81
81
80
5
4
j
15
16
17
18
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
6
4
6
a
b
The reaction was conducted on a 0.2 mmol scale. Isolated yield; the
4
7
numbers in the parentheses are the diastereomeric ratio (cis/trans)
k
c
determined by 19F NMR analysis. 2.0 equiv of BF3·Et2O was used.
19
20
24
0
l
15
79
6
a
b
The reaction was conducted using 0.2 mmol of 1a. Isolated yield.
was afforded in 41% yield (entry 10), indicating that a
carbocation intermediate was involved in the reaction. Polar
protic solvents like hexafluoro-2-propanol (HFIP) gave 45% of
the desired product 2a (entry 12). The employment of
ClCH2CH2Cl and CHCl3 did not show superior results
compared with that in CH2Cl2, producing 2a in 72% and
58% yields, respectively (entries 14 and 15). Further
investigation of the amount of BF3·Et2O and PhIO revealed
that 1.0 equiv of BF3·Et2O, and 2.0 equiv of PhIO was enough
for the present reaction, giving 2a in 80% yield within 4 h
(entry 18). We also tried Gouverneur’s conditions (1.1 equiv of
Selectfluor, 1.1 equiv of NaHCO3, CH3CN, rt, 48 h),7 but the
aminofluorination reaction did not occur since 1a was
recovered in 95% yield.
c
d
e
The recovery of 1a was 91%. The recovery of 1a was 93%. The
f
recovery of 1a was 92%. 1-Tosylpyrrolidin-3-yl acetate (3b) was
provided in 34% yield. 3c (a Ritter product, vide infra) was afforded
in 41% yield. The recovery of 1a was 95%. 3b was provided in 80%
g
h
i
j
k
yield. The conversion of 1a was 72%. The recovery of 1a was 88%.
l
1.5 equiv of PhIO was used.
fluorine-containing compounds such as AlF3, FeF3, CsF, SbF3,
and AgF, no reaction occurred and the starting material 1a was
almost recovered (entries 2−6). When BF3·THF was used, the
desired product 2a was obtained in 71% yield, a little lower
than the yield of BF3·Et2O (entry 7). The use of EtOAc as the
solvent led to 30% of the desired product 2a as well as 34% of
1-tosylpyrrolidin-3-yl acetate (3b) (entry 9). When CH3CN
was used, no desired product 2a was formed, whereas N-(1-
tosylpyrrolidin-3-yl)acetamide (3c, a Ritter product, vide infra)
After having optimized the reaction conditions, the substrate
scope was investigated (Table 2). When the N-protecting group
1443
dx.doi.org/10.1021/ol500238k | Org. Lett. 2014, 16, 1442−1445

Organic Letters
Letter
was tuned to p-nitrobenzenesulfonyl (Ns) or benzenesulfonyl
(Bs), the intramolecular aminofluorination reaction was run
smoothly, giving the corresponding 3-fluoropyrrolidine deriv-
atives 2b and 2c in 80% and 78% yields, respectively (Table 2,
entries 2 and 3). When ethyl, tert-butyl, phenyl, p-(tert-
butyl)phenyl, or m-trifluoromethylphenyl group was attached
to the α-carbon of the amino group, the desired products 2d−h
could be obtained in 82−88% yields, while the diastereomeric
ratio (cis/trans) varied from 4.3:1 to 6.0:1 (entries 4−8).
Notably, the gram-scale reaction of 1f could also give 2f in 76%
yield. For the substrate 1i with a cyano group at the α-carbon of
the amino group, the aminofluorination reaction gave 52% yield
of the desired product (entry 9), which might have potential
utility in the synthesis of a fibroblast activation protein inhibitor
compound II (Figure 1) and 3-fluorinated proline derivatives.
When a methyl or n-propyl group was attached to the allylic
position, the desired products 2j,k could be obtained in 70%
and 64% yields with moderate diastereoselectivity (entries 10
and 11). As for the substrate 1l bearing two methyl groups at
the allylic position, the desired aminofluorinated product 2l was
only obtained in 32% yield while dihydropyrrole product 3l was
formed in 14% yield, which came from a methyl shift process
(entry 12, vide infra). The reaction of aminoalkene 1m, in
which the C−C double bond and the amino group were
attached to a six-membered ring with a cis configuration
afforded bicyclic product 2m in 45% yield with a diastereomeric
ratio (cis/trans) of 5.8:1 (entry 13). For a 1,1-disubstituted
olefin 1o, the aminofluorination reaction proceeded smoothly
to produce 2o in 43% yield (entry 15). The configuration of
major isomers of products exemplified as 2e was confirmed to
be cis by their X-ray diffraction analysis (Figure 2) and NMR
spectra (for details, see the Supporting Information).
which reacted with 1a to give an iodonium intermediate B,
followed by the intramolecularly nucleophilic attack of the
amino group to generate an intermediate C. Then the
hypervalent iodine(III) intermediate C underwent reductive
elimination to afford a cyclic carbocation intermediate D.
Subsequently, this carbocation combined with fluoride ion
generated in situ to provide the product 2a. In the present
intramolecular aminofluorination reaction, BF3·Et2O played
dual roles; i.e., it activated iodosobenzene and more
significantly acted as the fluorine source.
Evidence was obtained to support the above mechanism.
When 1a reacted with PhIO in the presence of BF3·Et2O in
CH3CN, a Ritter product 3c was formed (Table 1, entry 10),
indicating that the presence of a carbocation intermediate
(Scheme 2a).20 Moreover, when 1l was treated with a PhIO/
Scheme 2. Explanation of the Formation of 3c and 3l
BF3·Et2O system, 14% of 3l was afforded. It was believed that
the formation of 3l would result from the rearrangement of the
key carbocation intermediate E (Scheme 2b).
Owing to the steric hindrance of the Ts group, one side of
the pyrrolidine ring was blocked. Thus, the attack of fluoride
ion from the opposite side of the pyrrolidine ring was favored,
which could account for the observed diastereoselectivity
(Scheme 3).
Scheme 3. Explanation of the Diastereoselectivity Observed
Figure 2. X-ray single-crystal structure of the cis isomer of 2e.
Scheme 1. Proposed Mechanism for the Intramolecular
Aminofluorination Reaction
In summary, we have developed a mild and efficient
intramolecular aminofluorination reaction of homoallylic
amines to provide 3-fluoropyrrolidines in which a commonly
used Lewis acid BF3·Et2O was utilized as the fluorine source
with PhIO as the oxidant. It was the first time that BF3·Et2O
acting as the fluorine source in a metal-free oxidative
transformation was disclosed. Considering the mild reaction
conditions, simple operation, and high yields, this method
represented an attractive way to synthesize 3-fluoropyrrolidines.
Moreover, the present work inspired us to explore more use of
safe, readily available, cheap, and easily handled fluorine-
A mechanism for the present intramolecular aminofluorina-
tion reaction was proposed (Scheme 1). First, PhIO was
activated by BF3·Et2O to form the iodine(III) intermediate A,
1444
dx.doi.org/10.1021/ol500238k | Org. Lett. 2014, 16, 1442−1445

Organic Letters
Letter
T.; Neumann, C. N.; Ritter, T. Angew. Chem., Int. Ed. 2013, 52, 8214−
8264.
containing compounds as the fluorine source in other oxidation
reactions.
(13) (a) Rueda-Becerril, M.; Sazepin, C. C.; Leung, J. C. T.;
Okbinoglu, T.; Kennepohl, P.; Paquin, J.-F.; Sammis, G. M. J. Am.
Chem. Soc. 2012, 134, 4026−4029. (b) Barker, T. J.; Boger, D. L. J.
Am. Chem. Soc. 2012, 134, 13588−13591. (c) Amaoka, Y.; Nagatomo,
M.; Inoue, M. Org. Lett. 2013, 15, 2160−2163.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details, characterization of new compounds, and
copies of 1H, 13C, and 19F NMR spectra, HRMS, and
crystallgraphic data. This material is available free of charge
via the Internet at http://pubs.acs.org.
(14) (a) Qiu, S.; Xu, T.; Zhou, J.; Guo, Y.; Liu, G. J. Am. Chem. Soc.
2010, 132, 2856−2857. (b) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature
2011, 473, 470−477. (c) Li, Z.; Song, L.; Li, C. J. Am. Chem. Soc. 2013,
135, 4640−4643. (d) Mazzotti, A. R.; Campbell, M. G.; Tang, P.;
Murphy, J. M.; Ritter, T. J. Am. Chem. Soc. 2013, 135, 14012−14015.
(15) (a) Edwards, J. A.; Ringold, H. J.; Djerassi, C. J. Am. Chem. Soc.
1960, 82, 2318−2322. (b) Mills, J. S.; Bowers, A.; Djerassi, C.;
Ringold, H. J. J. Am. Chem. Soc. 1960, 82, 3399−3404.
AUTHOR INFORMATION
■
Corresponding Author
(16) (a) Wei, Z. Y.; Wang, D.; Li, J. S.; Chan, T. H. J. Org. Chem.
*E-mail: zhangchi@nankai.edu.cn.
Notes
́
1989, 54, 5768−5774. (b) Wolfling, J.; Frank, E.; Schneider, G.; Bes,
̈
M. T.; Tietze, L. F. Synlett 1998, 1205−1206. (c) Al-Mutairi, E. H.;
Crosby, S. R.; Darzi, J.; Harding, J. R.; Hughes, R. A.; King, C. D.;
Simpson, T. J.; Smith, R. W.; Willis, C. L. Chem. Commun. 2001, 835−
The authors declare no competing financial interest.
́
́ ́
836. (d) Wolfling, J.; Frank, E.; Mernyak, E.; Bunkoczi, G.; Seijo, J. A.
̈
ACKNOWLEDGMENTS
■
C.; Schneider, G. Tetrahedron 2002, 58, 6851−6861. (e) Kataoka, K.;
Ode, Y.; Matsumoto, M.; Nokami, J. Tetrahedron 2006, 62, 2471−
2483. (f) Luo, H.-Q.; Hu, X.-H.; Loh, T.-P. Tetrahedron Lett. 2010, 51,
1041−1043.
This work was financially supported by The National Natural
Science Foundation of China (21172110 and 21121002). We
thank Prof. Jin Qu for helpful discussions.
(17) Yeh, M.-C. P.; Liang, C.-J.; Huang, T.-L.; Hsu, H.-J.; Tsau, Y.-S.
J. Org. Chem. 2013, 78, 5521−5529.
REFERENCES
■
(18) (a) De meio, G. V.; Pinhey, J. T. J. Chem. Soc., Chem. Commun.
1990, 1065−1066. (b) De meio, G.; Morgan, J.; Pinhey, J. T.
Tetrahedron 1993, 49, 8129−8138.
(1) (a) Bohm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.;
̈
Muller, K.; Obst-Sander, U.; Stahl, M. ChemBioChem 2004, 5, 637−
̈
643. (b) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881−
̈
(19) Yu, J.; Liu, S.-S.; Cui, J.; Hou, X.-S.; Zhang, C. Org. Lett. 2012,
14, 832−835.
1886. (c) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359−4369.
(2) Thayer, A. M. Chem. Eng. News 2006, 84 (23), 15−24.
(3) (a) Sharma, M.; Gupta, M.; Singh, D.; Kumar, M.; Kaur, P. Chem.
Biol. Drug. Des. 2013, 82, 156−166. (b) Tsai, T.-Y.; Yeh, T.-K.; Chen,
X.; Hsu, T.; Jao, Y.-C.; Huang, C.-H.; Song, J.-S.; Huang, Y.-C.; Chien,
C.-H.; Chiu, J.-H.; Yen, S.-C.; Tang, H.-K.; Chao, Y.-S.; Jiaang, W.-T. J.
Med. Chem. 2010, 53, 6572−6583.
(4) Asahina, Y.; Takei, M.; Kimura, T.; Fukuda, Y. J. Med. Chem.
2008, 51, 3238−3249.
(5) (a) Augustyns, K. J. L.; Lambeir, A. M.; Borloo, M.; De Meester,
(20) Ritter, J. J.; Minieri, P. P. J. Am. Chem. Soc. 1948, 70, 4045−
4048.
́
I.; Vedernikova, I.; Vanhoof, G.; Hendriks, D.; Scharpe, S.; Haemers,
A. Eur. J. Med. Chem. 1997, 32, 301−309. (b) Singh, R. P.; Shreeve, J.
M. Synthesis 2002, 17, 2561−2578. (c) Beaulieu, F.; Beauregard, L.-P.;
Courchesne, G.; Couturier, M.; LaFlamme, F.; L’Heureux, A. Org. Lett.
2009, 11, 5050−5053. (d) Umemoto, T.; Singh, R. P.; Xu, Y.; Saito, N.
J. Am. Chem. Soc. 2010, 132, 18199−18205. For the synthesis of
DAST, see: (e) von Halasz, S. P.; Glemser, O. Chem. Ber. 1970, 103,
594−602. (f) Middleton, W. J. J. Org. Chem. 1975, 40, 574−578.
(6) Lal, G. S.; Pez, G. P.; Pesaresi, R. J.; Prozonic, F. M.; Cheng, H. J.
Org. Chem. 1999, 64, 7048−7054.
(7) Combettes, L. E.; Lozano, O.; Gouverneur, V. J. Fluor. Chem.
2012, 143, 167−176.
(8) (a) Wu, T.; Yin, G.; Liu, G. J. Am. Chem. Soc. 2009, 131, 16354−
16355. (b) Wang, Q.; Zhong, W.; Wei, X.; Ning, M.; Meng, X.; Li, Z.
Org. Biomol. Chem. 2012, 10, 8566−8569. (c) Kong, W.; Feige, P.; de
Haro, T.; Nevado, C. Angew. Chem., Int. Ed. 2013, 52, 2469−2473.
(d) Huang, H.-T.; Lacy, T. C.; Błachut, B.; Ortiz, G. X., Jr.; Wang, Q.
Org. Lett. 2013, 15, 1818−1821. (e) Rauniyar, V.; Lackner, A. D.;
Hamilton, G. L.; Toste, F. D. Science 2011, 334, 1681−1684.
(f) Lozano, O.; Blessley, G.; del Campo, T. M.; Thompson, A. L.;
Giuffredi, G. T.; Bettati, M.; Walker, M.; Borman, R.; Gouverneur, V.
Angew. Chem., Int. Ed. 2011, 50, 8105−8109.
(9) Differding, E.; Ofner, H. Synlett. 1991, 187−189.
(10) (a) Banks, R. E. U.S. Patent 5,086,178, 1992. (b) Lal, G. S. J.
Org. Chem. 1993, 58, 2791−2796.
(11) Tang, P.; Wang, W.; Ritter, T. J. Am. Chem. Soc. 2011, 133,
11482−11484.
(12) (a) Singh, R. P.; Shreeve, J. M. Acc. Chem. Res. 2004, 37, 31−44.
(b) Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1−PR43. (c) Liang,
1445
dx.doi.org/10.1021/ol500238k | Org. Lett. 2014, 16, 1442−1445