Synthesis of β-fluoro amides using partially hydrated nickel difluoride as fluorine source

Article abstract of DOI:10.1055/S-0032-1317157

P-Fluoro amides were obtained from the reactions of activated aziridines with partially hydrated nickel difluoride (NiF₂-nH₂O, n <4) in good yields (47-82%) in the presence of tetran-butylammonium fluoride (20 mol%), while the non-ac

Full text of DOI:10.1055/S-0032-1317157

LETTER
▌2413
lSetyternthesis of β-Fluoro Amides Using Partially Hydrated Nickel Difluoride as
Fluorine Source
Fluorination using Hydrous Nickel Difluoride
Wan Xuan Zhang,* Li Su, Wei Gang Hu, Jie Zhou
Ministry of Education Key Laboratory for the Synthesis and Application of Organic Functional Molecules, Hubei University, Wuhan 430062,
P. R. of China
Fax +86(27)88663043; E-mail: zhangwx@hubu.edu.cn
Received: 14.06.2012; Accepted after revision: 30.07.2012
instead of MeCN, and relatively high yield (70%) of 2a
Abstract: β-Fluoro amides were obtained from the reactions of
was obtained (entry 2 in Table 1). The compound 4, re-
activated aziridines with partially hydrated nickel difluoride
sulting from the ring opening of aziridine 1a with water,7
(NiF2nH2O, n <4) in good yields (47–82%) in the presence of tetra-
was detected as the main by-product in the above reac-
tions. In order to inhibit the formation of 4, NiF24H2O
was treated into partially hydrated NiF2nH2O (n <4) be-
fore use by heating it in vacuum (5 mmHg) at 120 °C till
constant weight.8 When NiF2nH2O (n <4) was used in the
reaction, the yield of 2a increased to 82% within a shorter
time (entry 3 in Table 1). However anhydrous NiF2 from
Alfa Aesar were not fruitful to the reaction because the
polymerization of 1a led to a decreased yield of 2a (entry
6 in Table 1). If i-BuOH and t-BuOH were used as sol-
vents, the reaction was not improved (entries 4 and 5, re-
spectively, in Table 1).
n-butylammonium fluoride (20 mol%), while the non-activated
aziridines did not react under the same conditions.
Key words: nickel, fluorine, halogenation, ring opening, sulfon-
amide
β-Fluoro amides may act as drug candidates,1 or they can
be converted into β-fluoro amines which are important
compounds because of their functions in biological mole-
cules and catalysts.2 In contrast to the synthesis of β-fluo-
ro amine and its other derivatives,2,3 there have been fewer
reports documented in the literature describing methods
for the preparation of β-fluoro amides. The addition of N-
TBAF played an important role in the reaction though it
could not promote the reaction of KF2H2O with aziri-
dines.5 If TBAF was absent in the reaction of 1a with
NiF2nH2O, only trace of 2a was detected (entry 7 in Table
1). Further study indicated that reducing the amount of
NiF2nH2O in the reaction led to longer reaction time and
low yields of 2a.
1,3d
allylic sulfonamide with HF–SbF5 and the ring-open-
4
ing reaction of aziridines with BF3OEt2 or KF–
5
Bu4NHSO4 were efficient for the synthesis of β-fluoro
amides. However the reagents HF–SbF5 and BF3OEt2
have suffered from the fact that they are highly toxic or
corrosive to glass. Though KF–Bu4NHSO4 could smooth-
ly react with aziridines under mild conditions, Bu4NHSO4
did not act as a catalyst and 100 mol% of it should be add-
ed in the reaction; in addition, the reaction proceeded un-
der strong acidic condition, which may be harmful to the
aziridines bearing acid-sensitive group. Here we describe
a new procedure using partially hydrated nickel difluo-
ride, which is an inexpensive, non-toxic, ready available
inorganic salt, as fluorine source in the ring-opening reac-
tion of aziridines. β-Fluoro amides were obtained by treat-
ing activated aziridines (N-tosyl or N-acyl) with partially
hydrated nickel difluoride in the presence of 20 mol%
tetra-n-butylammonium fluoride (TBAF) under nearly
neutral conditions, while the non-activated aziridine (N-
alkyl) did not react under the same conditions.
Table 1 Conditions for the Reaction of 1a with Nickel Difluoride
NHTs
NHTs
OH
NiF2⋅nH2O (200 mol%)
NTs
TBAF, solvent
F
1a
2a
4
Entry Nickel salta
Solvent
T
(°C)
Time
(h)
Yield
(%)b
1
2
3
4
5
6
7c
NiF2·4H2O
NiF2·4H2O
NiF2·nH2O
NiF2·nH2O
NiF2·nH2O
NiF2
MeCN
i-PrOH
i-PrOH
t-BuOH
i-BuOH
i-PrOH
i-PrOH
reflux
90
46
24
12
13
60
24
12
50
70 (14)
82
90
90
75
The reaction was initially performed in MeCN using aziri-
dine 1a and commercially available hydrous nickel di-
fluoride (NiF24H2O) as substrates in the presence of
TBAF (20 mol%) under reflux, but only 50% of 2a was
obtained (entry 1 in Table 1). Inspired by the fact that al-
cohol could improve fluorination reactions using alkali
metal fluorides as substrates,6 2-propanol was employed
90
47
90
51
NiF2·nH2O
90
trace
a NiF2nH2O (n <4) was obtained by treating NiF24H2O in vacuum at
120 °C till constant weight, and its molecular weight was approximat-
ed as that of NiF24H2O.
b Isolated yield based on aziridine. The yield of 4 is given in parenthe-
sis.
SYNLETT 2012, 23, 2413–2415
Advanced online publication: 10.09.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
c TBAF was absent, but it (20 mol%) was added in the other reactions
(entries 1–6).
DOI: 10.1055/s-0032-1317157; Art ID: ST-2012-W0514-L
© Georg Thieme Verlag Stuttgart · New York

2414
W. X. Zhang et al.
LETTER
Table 2 The Results of the Reactions of Aziridines with Partially
Various aziridines were treated with NiF2nH2O (n <4) in
i-PrOH under reflux in the presence of TBAF (20 mol%).
The results are shown in Table 2. All the activated aziridi-
nes (with electron-withdrawing groups on nitrogen) de-
rived from cyclic and acyclic alkenes were suitable
substrates to provide the corresponding β-fluoro amides in
good to high yield (47–82%). Increasing the electron-
withdrawing ability of the group on nitrogen shortened the
reaction time or increased the yield of the corresponding
β-fluoro amide (entries 1–3 in Table 2); this behavior is
different from that of the reaction using BF3OEt2 as
fluorine source.4b
Hydrated Nickel Difluoridea (continued)
R1
F
R2
R1
R2
F
R1
R2
NiF2⋅nH2O (200 mol%)
+
NR3
TBAF (20 mol%)
i-PrOH, 90 °C
NHR3..
R3HN
1
2
3
Entry Substrateb
Product
Time
(h)
Yield
(%)c
(84:16)
n-Bu
F
NHTs
3g
Table 2 The Results of the Reactions of Aziridines with Partially
n-C16H33
n-C16H33
8
30
70
Hydrated Nickel Difluoridea
N
TsHN
2h
F
R1
F
R2
R1
R2
F
R1
R2
NiF2⋅nH2O (200 mol%)
Ts
+
NR3
TBAF (20 mol%)
i-PrOH, 90 °C
1h
NHR3..
R3HN
1
2
3
n-C16H33
(77:23)
F
Entry Substrateb
Product
Time
(h)
Yield
(%)c
TsHN
3h
H
1
12
82
NHTs
9
12
12
0
N
NTs
N
F
F
1a
1b
1c
1i
1j
2a
2b
2c
2i
2j
NHBs
F
2
3
4
5
33
36
80
63
64
NHBn
F
10
0
NBs
NBz
NBn
NBz
F
a NiF2nH2O (n <4) was obtained by treating NiF24H2O in vacuum at
120 °C till constant weight, and its molecular weight was approximat-
ed as that of NiF24H2O.
b Ts = p-MeC6H4SO2, Bs = PhSO2, Bz = PhCO, Bn = CH2Ph.
c Isolated yield based on aziridine. Ratios of the two regioisomers 2
and 3 given in parenthesis were determined by 600 MHz 1H NMR.
BzCl-p
NHBzCl-p
N
F
The regioselectivities for the reactions of monosubstituted
aziridines were similar to those of the reactions using KF
as fluorine source in the presence of Bu4NHSO4.5 Phenyl
aziridine 1f reacted with NiF2nH2O leading to two iso-
mers 2f and 3f, with the isomer 3f with a fluorine atom at
secondary carbon being the main product (entry 6 in Table
2). The reaction of terminal alkyl aziridine 1g (or 1h) pro-
vided two products 2g and 3g (or 2h and 3h), respectively,
and the regioisomer 2g (or 2h) resulting from the attack of
fluorine atom at the less substituted carbon was obtained
as the main product (entries 7 and 8 in Table 2). When N-
allyl and N-Bn aziridines (1i and 1j) derived from cyclo-
hexene, which were non-activated, were used as sub-
strates, the reaction did not occur (entries 9 and 10 in
Table 2).
2d
2e
1d
1e
NHTs
F
5
6
24
27
57
47
NTs
Ph
NTs
TsHN
F
2f
1f
Ph
F
(34:66)
70
NHTs
3f
n-Bu
In conclusion, partially hydrated nickel difluoride
(NiF2nH2O, n <4) was demonstrated an effective reagent
for the fluorination of aziridine with electron-withdraw-
ing group on nitrogen in i-PrOH catalyzed by TBAF (20
mol%).9 A facile method for the preparation of β-fluoro
n-Bu
7
14
N
TsHN
F
Ts
2g
1g
Synlett 2012, 23, 2413–2415
© Georg Thieme Verlag Stuttgart · New York

LETTER
Fluorination using Hydrous Nickel Difluoride
2415
(5) Fang, R. H.; Zhou, Y. G.; Zhang, W. X.; Hou, X. L.; Dai,
L. X. J. Org. Chem. 2004, 69, 335.
(6) (a) Lee, S. J.; Oh, S. J.; Chi, D. Y.; Lee, B. S.; Ryu, J. S.;
Moon, D. H. J. Label Compd. Radiopharm. 2008, 51, 80.
(b) Kim, D. W.; Ahn, D. S.; Oh, Y. H.; Lee, S.; Kil, H. S.
J. Am. Chem. Soc. 2006, 128, 16394.
(7) Fang, R. H.; Hou, X. L. Org. Biomol. Chem. 2003, 1, 1565.
(8) Complete dehydration of NiF24H2O needs vigorous
condition: heating it to 500 °C under an atmosphere of HF.
(9) Typical Procedure for the Ring Opening of Aziridine
with Partially Hydrated Nickel Difluoride: To a stirred
solution of aziridine 1a (0.5 mmol) and partially hydrated
nickel difluoride (NiF2nH2O, n <4, 1.68 g, approx. 1 mmol)
in i-PrOH (3.0 mL) was added Bu4NF (0.1 mmol), and
the mixture was stirred at 90 °C until 1a was consumed
(monitored by TLC). The mixture was filtered by short silica
gel column and washed with CH2Cl2, then the solvent was
removed in vacuum and the residue was purified by flash
column chromatography on silica gel to yield 2a as a white
amorphous solid.
amide under nearly neutral condition using safe and easy-
to-handle fluorine source was developed.
Acknowledgment
This research was financially supported by the National Natural
Science Foundation of China (No. 20872031).
References
(1) Liu, F.; Martin-Mingot, A.; Jouannetaud, M.-P.; Zunino, F.;
Thibaudeau, S. Org. Lett. 2010, 13, 868.
(2) (a) Purser, S.; Moore, P. M.; Swallow, S.; Gouverneur, V.
Chem. Soc. Rev. 2008, 37, 320. (b) Zimmer, L. E.; Sparr, C.;
Gilmour, R. Angew. Chem. Int. Ed. 2011, 50, 11860.
(c) Hagmann, W. H. J. Med. Chem. 2008, 51, 4359. (d) Kirk,
K. L. Org. Process Res. Dev. 2008, 12, 305.
(3) (a) Hakman, S.; Beguin, C. G. J. Fluorine Chem. 1987, 37,
343. (b) Toulgui, C.; Chaabouni, M. M.; Baklouti, A.
J. Fluorine Chem. 1990, 46, 385. (c) D’hooghe, M.; De
Kimpe, N. Synlett 2006, 2089. (d) Thibaudeau, S.; Martin-
Mingot, A.; Jouannetaud, M.-P.; Karam, O.; Zunino, F.
Chem. Commun. 2007, 3198. (e) Jing, Z. T.; Huang, Y. G.;
Qing, F. L. Chin. Chem. Lett. 2011, 22, 919. (f) Schulte,
M. L.; Lindsley, C. W. Org. Lett. 2011, 13, 5684.
N-(2-Fluorocyclohexyl)-4-methylbenzenesulfonamide
(2a): 82% yield; mp 95–96 °C (lit.5 95–97 °C). 1H NMR
(600 MHz, CDCl3, 25 °C, TMS): δ = 1.22–1.26 (m, 4 H),
1.57–1.70 (m, 2 H), 2.01–2.13 (m, 2 H), 2.43 (s, 3 H), 3.17
(m, 1 H), 4.15, 4.25 (double multiplet, 2JHF = 50.1 Hz, 1 H),
4.81 (d, J = 5.4 Hz, 1 H), 7.30 (d, J = 7.8 Hz, 2 H), 7.76 (d,
J = 8.4 Hz, 2 H). 19F NMR (600 MHz, CDCl3, 25 °C,
CF3COOH): δ = –179.3. IR (KBr): 3302, 2951, 1598, 1327,
1163, 1091, 1045, 893, 816, 667, 572, 551 cm–1.
(4) (a) Hu, X. E. Tetrahedron 2004, 60, 2701. (b) Ding, C.-H.;
Dai, L.-X.; Hou, X.-L. Synlett 2004, 2218.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2413–2415