An efficient and highly regioselective fluorination of aziridines using BF3·OEt2 as fluorine source

Article abstract of DOI:10.1055/s-2004-831319

β-Fluoro amines were prepared from the reaction of aziridines and boron trifluoride in high regioselectivity and in high yield. All three fluorine atoms of BF₃·OEt₂ were incorporated into the products when it reacted with aziridines.

Full text of DOI:10.1055/s-2004-831319

2218
LETTER
An Efficient and Highly Regioselective Fluorination of Aziridines Using
BF3·OEt2 as Fluorine Source
R
egioselective Fl
h
uorination of
a
A
ziridinesng-Hua Ding,b Li-Xin Dai,a Xue-Long Hou*a,b
a
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin
Road, Shanghai 200032, P. R. China
b
Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, P. R. China
E-mail: xlhou@mail.sioc.ac.cn
Received 21 June 2004
the absence of (–)-menthol, the reaction completed in 48
hours and b-fluoro amine 2a was also provided in 73%
yield. Obviously, BF3 serves as the reagent to provide the
fluoride in this reaction and the alcohol accelerated the re-
action. The optimization of the reaction conditions
showed that i-PrOH is a more efficient additive than
MeOH or t-BuOH and CH2Cl2 is a better solvent among
Et2O, toluene or THF, in which the yield increased to
83%.
Abstract: b-Fluoro amines were prepared from the reaction of azir-
idines and boron trifluoride in high regioselectivity and in high
yield. All three fluorine atoms of BF3·OEt2 were incorporated into
the products when it reacted with aziridines.
Key words: aziridines, fluorination, BF3·OEt2, ring-opening reac-
tion, b-fluoro amine
BF3·OEt2 is one of the most common Lewis acids and
widely used as catalyst in numerous organic transforma-
tions, such as polymerization, alkylation, isomerization,
condensation, and degradation,1 but is rarely used as fluo-
rine source in fluorination reactions.2 On the other hand,
the introduction of a fluorine atom into organic molecules
has received much interest due to the physical and biolo-
gical properties of fluorine-containing organic mole-
cules.3 Usually monofluorination is realized using
NHTs
BF3·OEt2
NTs
+
CH2Cl2
F
OH
1a
2a
Scheme 1
diethylaminosulfurtrifluoride (DAST), tris(diethylami- In this reaction, BF3·OEt2 is the only fluorine source. It
no)sulfonium difluorotrimethylsilicate (TAS-F), com- was noted that there are three fluorine atoms in BF3·OEt2.
plexes of hydrogen fluoride with organic bases as Then we were interested to know whether the transforma-
reagents.4 Recently, a facile ring-opening reaction of tion of the second or even the third fluorine atom to aziri-
aziridines to b-fluoro amines using KF in the presence of dine is possible. So various amounts of BF3·OEt2 and i-
Bu4NHSO4 was developed in our groups.5 However, the PrOH were used to test the possibility and the results are
reaction suffered from low regioselectivity for monosub- showed in Table 1.
stituted aziridines. During the course of studies on the
transformation of aziridines,6 we tried to use BF3·OEt2 as
Table 1 Reaction of Aziridine 1a with BF3·OEt2 in the Presence of
i-PrOH under Various Reaction Conditions
the catalyst in the reaction of aziridines. It was surprising
NHTs
to find that ring-opening products of aziridines from fluo-
rine attack were separated in high regioselectivity and in
high yield. Additionally, all three fluorine atoms of BF3
were transformed into the products efficiently.7 In this let-
iPrOH
+
NTs
BF3·OEt2
CH2Cl2
F
1a
2a
ter, we would like to report our preliminary results on the Entry
BF3·OEt2
(equiv)
i-PrOH
(equiv)
Time
(h)
Yield
(%)a
preparation of b-fluoro amines from ring-opening reac-
tion of aziridines using BF3 as fluorine source.
1
1.0
1.0
1
12
83
80
87
82
78
63
In an attempted ring-opening reaction of aziridine 1a with
(–)-menthol in the presence of 1.0 equivalent BF3·OEt2,
2
0.50
0.40
0.35
0.35
0.25
0.50
0.40
0.35
0
the reaction was completed in two hours. However, no
corresponding ring-opening product of aziridine from (–)-
menthol attack was obtained. Instead, an unexpected b-
fluoro amine 2a was isolated in 63% yield (Scheme 1). In
3
4
5
6
26
26
120
76
0.25
SYNLETT 2004, No. 12, pp 2218–2220
Advanced online publication: 31.08.2004
0
1
.1
0
.2
0
0
4
a Isolated yields based on aziridine.
DOI: 10.1055/s-2004-831319; Art ID: U17704ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Regioselective Fluorination of Aziridines
2219
Indeed, all three fluorine atoms can be transformed into in good to high yield when the reaction proceed using 0.35
the ring-opening product of aziridine as shown in Table 1. equivalents of BF3·OEt2 in the presence of 0.35 equiva-
When the amount of BF3·OEt2 and i-PrOH was decreased lents of i-PrOH in CH2Cl2. The important feature of the re-
to 50 mol% in reaction mentioned above, 80% yield of b- action is its high regioselectivity. The reaction for all
fluoro amine 2a was obtained after 12 hours (entry 2). aziridines derived from acyclic alkenes gave only one
Then the amount of both BF3·OEt2 and i-PrOHwas further regioisomer, resulting from fluoride attack at the more
reduced to 40 mol%, 35 mol% and 25 mol%, b-fluoro substituted carbon atom of the aziridines. This regioselec-
amine 2a was separated in 87%, 82% and 63% yield, re- tivity differs not only from that using KF in the presence
spectively, with longer reaction time (entry 3, 4 and 6). of Bu4NHSO4 reported recently by us,5 in which two iso-
These results suggested that all three fluorine atoms in mers were obtained resulting from the attack of fluoride to
BF3·OEt2 could be transformed to the ring-opened product both carbons of aziridine ring, but also from that of ring-
of aziridine. It was also noted that the presence of alcohol opening reaction of aziridines using Lewis acid as cata-
is important, in the absence of alcohol the reaction needed lyst.8 However when non-activated aziridine was used as
120 hours to completion (entry 5).
substrate, reaction didn’t occur.
When enantiomerically pure monosubstituted N-tosyl-
aziridine (S)-1g prepared by the method of Craig10 was
used as substrate, corresponding product (S)-2g was ob-
tained without the loss of ee value (Scheme 2). Obviously
this procedure provides an easy and simple but efficient
way to chiral b-fluoro amine.
Table 2 The Ring-Opening of Aziridines with BF3·OEt2 in the Pres-
ence of i-PrOH
R1
R2
R2
R1
iPrOH (0.35 equiv)
CH2Cl2, 25 °C
+
BF3·OEt2
NR3
R3HN
F
0.35 equiv
2a–h
1a–h
iPrOH (0.35 equiv)
F
Entry Substratea
Product
Time (h) Yield (%)b
+
NTs
BF3·OEt2
NHTs
Bn
CH2Cl2, 25 °C
0.35 equiv
1
26
20
25
82
49
68
NHTs
F
Bn
NTs
(S)–2g
67% yield, 93% ee
(S)–1g
1a
2a
2b
2c
2
NHTs
F
Scheme 2
NTs
1b
In conclusion, we have demonstrated that BF3 is a good
fluorine source and all three fluorine atoms are used in the
facile ring-opening reactions of aziridines to b-fluoro
amines. The reactions afforded b-fluoro amines with ex-
cellent regioselectivity. Although the detailed reaction
mechanism is not clear at moment, the highly regioselec-
tivity of the reaction implies that this fluoride-transfer re-
action proceeds in an unusual way. Investigations of the
mechanism and the asymmetric version of the reaction are
in progress.
3
NHBs
F
NBs
1c
4
19
23
36
28
51
67
83
68
F
NTs
NHTs
NHTs
NHTs
n-C4H9
n-C4H9
1d
2d
5
6
7
F
NTs
NTs
n-C6H13
n-C6H13
1e
2e
F
n-C16H33
n-C16H33
Acknowledgment
1f
2f
We are grateful for financial support from the National Natural Sci-
ence Foundation of China, the Major Basic Research Development
Program (Grant No. G2000077506), National Outstanding Youth
Fund, Chinese Academy of Sciences and Shanghai Committee of
Science and Technology. CDH gratefully acknowledged Hong
Kong Croucher Foundation for a Studentship.
F
NTs
Ph
Ph
NHTs
1g
2g
a Ts = p-CH3C6H4SO2, Bs = C6H5SO2.
b Isolated yield based on aziridine.
Varies of aziridines were used to test the ability of this
fluoride-transfer reaction using BF3·OEt2 as fluorine
source and the results are shown in Table 2.9 It can be seen
that all aziridines derived from cyclic and acyclic alkenes
with electronic-withdrawing groups on nitrogen are suit-
able substrates to provide corresponding b-fluoro amines
References
(1) (a) Topchiev, A. V.; Zavgorodnii, S. V.; Paushkin, Ya. M.
Boron Fluoride and its Compounds as Catalysts in Organic
Chemistry; Pergamon Press: New York, 1959. (b) Booth,
H. S.; Martin, D. R. Boron Trifluoride and its Derivatives;
Wiley: New York, 1949.
Synlett 2004, No. 12, 2218–2220 © Thieme Stuttgart · New York

2220
C.-H. Ding et al.
LETTER
N-(2-Fluorohexyl)-4-methylbenzenesulfonamide (2d):
(2) (a) Voronkov, M. G.; Fedotova, L. A. Khim. Geterotsikl.
Soedin. 1966, 545. (b) Legters, J.; Willems, J. G. H.; Thijs,
L.; Zwanenburg, B. Recl. Trav. Chim. Pays-Bas 1992, 111,
59. (c) Heasley, G. E.; Janes, J. M.; Stark, S. R.; Robinson,
B. L. Tetrahedron Lett. 1985, 26, 1811. (d) Henbest, H. B.;
Wrigley, T. I. J. Chem. Soc. 1957, 4765. (e) Bowers, E.;
Ringold, H. J. Tetrahedron 1958, 3, 14. (f) Reddy, R.;
Jaquith, J. B.; Neelagiri, V. R.; Hanna, S. S.; Durst, T. Org.
Lett. 2002, 4, 695. (g) Sugihara, Y.; Iimura, S.; Nakayama,
J. Chem. Commun. 2002, 134.
51% yield; white solid; mp 62–63 °C. 1H NMR (300 MHz,
CDCl3, 25 °C, TMS): d = 0.88 (t, J = 6.6 Hz, 3 H), 1.27–1.63
(m, 6 H), 2.44 (s, 3 H), 2.93–3.08 (m, 1 H), 3.20–3.31 (m, 1
H), 4.43 and 4.60 (double multiplet, 2JH-F = 51.0 Hz, 1 H),
4.78 (dd, J = 4.8, 7.2 Hz, 1 H), 7.32 (d, J = 7.8 Hz, 2 H), 7.75
(d, J = 8.7 Hz, 2 H). 19F NMR (282 MHz, CDCl3, 25 °C,
CF3COOH): d = –186.4 (m). MS (EI): m/z (%) = 273
(1.63)(M+), 184 (80), 155 (100), 91 (85). IR (film): 3279,
1599, 1496 cm–1.
(3) (a) Seebach, D. Angew. Chem., Int. Ed. Engl. 1990, 29,
1320. (b) Filler, R. Studies in Organic Chemistry, In
Organofluorine Compounds in Medicinal Chemistry and
Biomedical Applications, Vol. 48; Filler, R., Ed.; Elsevier:
New York, 1993. (c) Percy, J. M. Contemporary Organic
Synthesis 1995, 251.
(4) For reviews on the formation of the C-F bond see:
(a) Mascaretti, O. E. Aldrichimica Acta 1993, 26, 47.
(b) Wilkinson, J. A. Chem. Rev. 1992, 92, 505. (c) Yoneda,
N. Tetrahedron 1991, 47, 5329.
N-(2-Fluorooctyl)-4-methylbenzenesulfonamide (2e):
67% yield; white solid; mp 72–73 °C. 1H NMR (300 MHz,
CDCl3, 25 °C, TMS): d = 0.88 (t, J = 6.9 Hz, 3 H), 1.25–1.60
(m, 10 H), 2.44 (s, 3 H), 2.94–3.09 (m, 1 H), 3.21–3.32 (m,
1 H), 4.43 and 4.59 (double multiplet, 2JH-F = 48.6 Hz, 1 H),
4.75 (dd, J = 4.8, 7.5 Hz, 1 H), 7.32 (d, J = 8.1 Hz, 2 H), 7.75
(d, J = 8.4 Hz, 2 H). 19F NMR (282 MHz, CDCl3, 25 °C,
CF3COOH): d = –173.9 (m). MS (EI): m/z (%) = 301 (1.19)
[M+], 184 (99), 155 (100), 146 (12), 91 (95). IR (film): 3276,
1600, 1324, 1160 cm–1. Anal. Calcd for C15H24FNO2S: C,
59.77; H, 8.03; N, 4.65. Found: C, 59.73; H, 7.97; N, 4.54.
N-(2-Fluorooctadecyl)-4-methylbenzenesulfon-amide
(2f): 83% yield; white solid; mp 82–83 °C. 1H NMR (300
MHz, CDCl3, 25 °C, TMS): d = 0.88 (t, J = 6.6 Hz, 3 H),
1.25–1.58 (m, 30 H), 2.44 (s, 3 H), 2.93–3.08 (m, 1 H), 3.13–
3.31 (m, 1 H), 4.42 and 4.58 (double multiplet, 2JH-F = 49.2
Hz, 1 H), 4.71 (dd, J = 4.8, 7.8 Hz, 1 H), 7.32 (d, J = 8.1 Hz,
2 H), 7.74 (d, J = 8.1 Hz, 2 H). 19F NMR (282 MHz, CDCl3,
25 °C, CF3COOH): d = –186.6 (m). MS (EI): m/z (%) = 441
(1.14) [M+], 286 (35), 184 (100), 155 (59), 91 (37). IR (film):
3290, 1927, 1600, 1334, 1163 cm–1. Anal. Calcd for
C25H44FNO2S: C, 67.98; H, 10.04; N, 3.17. Found: C, 68.23;
H, 9.85; N: 3.20.
(S)-N-(2-Fluoro-3-phenylpropyl)-4-methylbenzene-
sulfonamide (2g): 68% yield; white solid; mp 131–132 °C.
1H NMR (300 MHz, CDCl3, 25 °C, TMS): d = 2.43 (s, 3 H),
2.84–3.27 (m, 4 H), 4.59–4.83 (m, 1 H), 4.75–4.83 (m, 1 H),
7.14 (d, J = 6.6 Hz, 2 H), 7.25–7.32 (m, 5 H), 7.71 (d, J = 8.1
Hz, 2 H). 19F NMR (282 MHz, CDCl3, 25 °C, CF3COOH):
d = –184.5 (m). MS (EI): m/z (%) = 308 (0.64) [M + 1]+, 132
(100), 155 (41), 91 (94). IR (film): 3284, 1928, 1598, 1315,
1162 cm–1. Anal. Calcd for C16H18FNO2S: C, 62.52; H, 5.90;
N, 4.56. Found: C, 656; H, 6.08; N: 4.52.
(5) Fan, R. H.; Zhou, Y. G.; Zhang, W. X.; Hou, X. L.; Dai, L.
X. J. Org. Chem. 2004, 69, 335.
(6) (a) Wu, J.; Hou, X. L.; Dai, L. X. J. Org. Chem. 2000, 65,
1344. (b) Hou, X. L.; Fan, R. H.; Dai, L. X. J. Org. Chem.
2002, 67, 5295. (c) Fan, R. H.; Hou, X. L. J. Org. Chem.
2003, 68, 726. (d) Fan, R. H.; Hou, X. L.; Dai, L. X. J. Org.
Chem. 2004, 69, 689.
(7) Hu’s group reported similar result but only one example was
present and 2.0 equiv of BF3·OEt2 was used: Hu, X. E.
Tetrahedron Lett. 2002, 43, 5315.
(8) For recent review on nucleophilic ring-opening of aziridines
see: Hu, X. E. Tetrahedron 2004, 60, 2701.
(9) General Procedure of the Reaction of Aziridine 1 with
BF3·OEt2 in the Presence of Alcohol: To a stirred solution
of aziridine 1 (0.5 mmol) and alcohol in corresponding
solvent (2.0 mL) was added BF3·OEt2 (0.6 mmol) under
argon. The resulting mixture was stirred at 25 °C till
complete consumption of substrate (monitored by TLC).
The reaction mixture was quenched with 5 mL of sat. NH4Cl
aq solution. The aqueous layer was separated and extracted
with CH2Cl2 (3 × 10 mL). The combined organic layer was
dried over anhyd Na2SO4. The solvent was removed in
vacuum and the crude product was purified by flash column
chromatography on silica gel to provide corresponding b-
fluoro amines.5 The analytical data of some products are
shown below:
(10) Berry, M. B.; Craig, D. Synlett 1992, 41.
Synlett 2004, No. 12, 2218–2220 © Thieme Stuttgart · New York