Synthesis of (fluoroalkyl)amines by deoxyfluorination of amino alcohols

Article abstract of DOI:10.1055/s-2006-947316

Deoxyfluorination of amino alcohols was achieved using N,N-diethyl-α, α-difluorobenzylamine (DFBA) to furnish N-benzoyl(fluoroalkyl)amines selectively. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-947316

1744
LETTER
Synthesis of (Fluoroalkyl)amines by Deoxyfluorination of Amino Alcohols
S
ynthesisof (Fl
a
uoroalkyl)a
k
mines ashi Nomoto, Tsuyoshi Fukuhara, Shoji Hara*
Graduate School of Engineering, Hokkaido University, Sapporo, 060-8628 Japan
Fax +81(11)7066556; E-mail: shara@eng.hokudai.ac.jp
Received 31 March 2006
F
Abstract: Deoxyfluorination of amino alcohols was achieved
using N,N-diethyl-a,a-difluorobenzylamine (DFBA) to furnish N-
benzoyl(fluoroalkyl)amines selectively.
PhCF2NEt2
DFBA
NPh
O
F
NPh
Bz
HO
NHPh
70 °C, 10 min
Key words: amino alcohols, fluorination, deoxygenation, substitu-
tion, N,N-diethyl-a,a-difluorobenzylamine
2a
1a
Ph
85%
3
DFBA
Introduction of fluorine atoms into biologically active
amines1 and amino acids2 is of great interest to medicinal
chemists because the fluorine atom reduces the basicity of
the amino group and modifies their metabolism and phar-
macological properties. Furthermore, due to the develop-
ment of 18F-labelled compounds for positron emission
tomography (PET),3 the importance of the (fluoro-
alkyl)amine synthesis has increased remarkably.
N
O
+
F
NHBz
HO
NH2
15%
Ph
4
30%
Scheme 1
2-(Benzylamino)ethanol (1b) was less reactive than 1a
and the corresponding (fluoroalkyl)amide (2b) was ob-
tained in 70% yield by reaction with DFBA at 100 °C for
ten minutes (Table 1). The fluorination of the sec-hydroxy
group of amino alcohols 1c–e by DFBA also proceeded to
give the corresponding (fluoroalkyl)amides 2c–e in good
yields. Fluorination of a g-amino alcohol is also possible
and 3-(benzylamino)-1-propanol (1f) could be converted
to the corresponding (g-fluoroalkyl)amide 2f in 71%
yield. In the reaction with cis-2-(benzylamino)cyclohex-
anol (1g), N-benzyl-N-(trans-2-fluorocyclohexyl)benz-
amide (2g) was obtained in moderated yield and the
formation of an olefinic by-product was observed. On the
other hand, only a complex mixture was formed in the
reaction of trans-2-(benzylamino)cyclohexanol with
DFBA. When trans-2-(dibenzylamino)cyclohexanol (1h)
was used, the fluorination took place with retention of
stereochemistry and N,N-dibenzyl(trans-2-fluorocyclo-
hexyl)amine (2h) was obtained in high yield. In the case
of N,N-disubstituted amino alcohols, the reaction must
proceed through an aziridinium intermediate instead of
the oxazolinium 3.15
Fluoroamines can be prepared from amino alcohols via
cyclic sulfamidates;4 however, it includes multi-step
procedures and requires a long reaction time. Due to the
short half-life of 18F,5 it is desirable to synthesize them as
rapidly as possible, and a more direct method is required.
Though the deoxyfluorination reaction of amino alcohols
is the most suitable method for their synthesis, the
application of deoxyfluorination reagents, such as diethyl-
aminosulfur trifluoride (DAST)4e,6 or bis(2-methoxy-
ethyl)aminosulfur trifluoride (Deoxofluor),7 often results
in undesired side reactions. Recently, we reported the
deoxyfluorination reactions of alcohols,8 diols,9
aldehydes,10 and epoxides11 using N,N-diethyl-a,a-di-
fluoro-(m-methylbenzyl)amine (DFMBA). We wish to
report here that amino alcohols can be directly converted
to N-benzoyl(fluoroalkyl)amines by N,N-diethyl-a,a-di-
fluorobenzylamine (DFBA).12
When 2-(phenylamino)ethanol (1a) was allowed to react
with 2.4 equivalents of DFBA without solvent at 70 °C
using conventional oil bath heating or microwave irradia-
tion, the reaction was complete in 10 minutes and N-(2-
fluoroethyl)-N-phenylbenzamide (2a) was obtained in
85% yield.14 A hydroxyl group in 1a was converted to a
fluoride while an amino group was acylated by DFBA.
The reaction must proceed through an oxazolinium inter-
mediate 3 as in the case of diols.9 It was supported by the
formation of oxazoline derivative 4 in the reaction of 2-
aminoethanol with DFBA (Scheme 1).
Various optically active amino alcohols are easily ac-
cessible and can be converted into the corresponding
optically active (fluoroalkyl)amides by DFBA. Thus, (S)-
N-benzyl-N-(1-fluoromethyl-2-phenylethyl)benzamide
(2k) and (S)-N-benzyl-N-(1-fluoromethyl-3-methyl-
butyl)benzamide (2l) could be prepared optically active
from the corresponding optically active amino alcohols
1k and 1l in 78% and 86% yields, respectively.
Enantiomerically pure (S)- and (R)-(2-fluoro-1-methyl-
ethyl)amines (5) were required for the synthesis of b-
adrenoceptor ligands, and were prepared from the corre-
sponding 2-(benzylamino)-1-propanol (1j) in a multi-step
SYNLETT 2006, No. 11, pp 1744–1746
Advanced online publication: 04.07.2006
DOI: 10.1055/s-2006-947316; Art ID: U03806ST
© Georg Thieme Verlag Stuttgart · New York
1
2
.0
7
.2
0
0
6

LETTER
Synthesis of (Fluoroalkyl)amines
1745
Table 1 Fluorination of Amino Alcohols Using DFBAa
Amino alcohol
Reaction conditions
Product
Yield (%)b
H
N
Bz
100 °C, 10 minc
100 °C, 10 min
100 °C, 10 min
100 °C, 10 min
100 °C, 10 min
70
76
96
76
71
Bn
OH
N
Bn
F
1b
2b
Bz
F
F
F
OH
OH
H
N
N
Bn
Hex
Hex
Bn
Hex
Hex
1c
2c
Bz
H
N
N
Ph
Ph
1d
2d
OH
Bz
H
N
OBz
N
OBz
Bn
Bn
1e
2e
Bz
H
N
OH
Bn
N
F
Bn
1f
2f
OH
F
100 °C, 10 min
55
NH
Bn
NBz
Bn
1g
1h
2g
OH
F
100 °C, 10 min
100 °C, 10 min
94
78
NBn2
NBn2
2h
H
N
Bz
N
Bn
OH
Bn
F
Bn
Bn
1k
2k
Bz
N
H
N
100 °C, 10 min
86
Bn
F
Bn
OH
iBu
iBu
2l
1l
a Unless otherwise stated, the reaction was carried out with DFBA (2.4 equiv) and 1 (1 equiv) without solvent.
b Isolated yield based on 1.
c Dioxane was used as the solvent.
H2N
H2N
synthesis via cyclic sulfamidates in 21% and 26% overall
yields, respectively.4e When (S)- or (R)-1j was treated
with 2.4 equivalents of DFBA at 100 °C, the reaction was
complete in 10 minutes and the corresponding (S)- or (R)-
N-benzyl-N-(2-fluoro-1-methylethyl)benzamide (2j) was
obtained in 84% and 86% yields, respectively. After re-
moval of the protecting groups, the desired (S)- or (R)-(2-
fluoro-1-methylethyl)amine (5) was obtained enantiomer-
ically pure in 59% and 56% overall yields, respectively
(Scheme 2).
F
F
F
Me
Me
(S)-5
(R)-5
Bz
H
N
1) LiAlH4
2) Pd/C
DFBA
N
(S)-5 HCl
Bn
Bn
Bn
OH
OH
3) HCl
70%
100 °C,
10 min
Me
Me
(S)-2j
(S)-1j
84%
Bz
H
N
1) LiAlH4
2) Pd/C
DFBA
N
Bn
F
(R)-5 HCl
100 °C,
10 min
3) HCl
65%
Me
(R)-2j
Me
(R)-1j
86%
Scheme 2
Synlett 2006, No. 11, 1744–1746 © Thieme Stuttgart · New York

1746
T. Nomoto et al.
LETTER
(11) Yu, H.-W.; Nakano, Y.; Fukuhara, T.; Hara, S. J. Fluorine
Chem. 2005, 126, 962.
References and Notes
(12) Due to the enolizable character of the amide function,13 the
NMR spectra of the N-acylated products 2 were sometimes
complicated and reduction of the amide function to the
amine was necessary for analysis. When DFBA was used for
the reaction with N-benzylamino alcohols, N,N-
(1) (a) Coutts, R. T.; Benderly, A.; Mak, A. L. C. J. Fluorine
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Clark, J. E.; Murphy, B. L.; Fischer, P. A. J. Org. Chem.
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(2) (a) Fluorine-Containing Amino Acids; Kukhar, V. P.;
Soloshonok, V. A., Eds.; Wiley: Chichester, 1995. (b) Qiu,
X.-L.; Meng, W.-D.; Qing, F.-L. Tetrahedron 2004, 60,
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dibenzylamine derivatives were formed after the reduction,
and their NMR spectra are simpler than that of the product
from DFMBA. Therefore, DFBA was used instead of
DFMBA. DFBA showed reactivity comparable with
DFMBA and can be prepared from N,N-diethylbenzamide as
DFMBA.10
(3) (a) Chi, D. Y.; Kilbourn, M. R.; Katzenellenbogen, J. A.;
Welch, M. J. J. Org. Chem. 1987, 52, 658. (b) Lyle, T. A.;
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(14) To a reactor with a TeflonTM PFA tube with a diameter of 10
mm sealed at one end, 1a (137 mg, 1 mmol) and DFBA (478
mg, 2.4 mmol) were introduced. The open end of the reactor
was connected to a reflux condenser. Then, the reactor part
was submitted to microwave-irradiation (IDX microwave
oven for organic synthesis IMCR-25003) for 10 min and
during the irradiation the temperature was kept at 70 °C.
After cooling, the reaction mixture was poured into an aq
solution of NaHCO3. The product was extracted with Et2O
(3 ×) and the combined ethereal layers were dried over
MgSO4. Purification by column chromatography (silica gel,
hexane–Et2O) gave 2a (207 mg, 0.85 mmol) in 85% yield.
N-(2-Fluoroethyl)-N-phenylbenzamide (2a): IR (neat):
1649, 1494, 1377 cm–1. 1H NMR: d = 7.32–7.09 (m, 10 H),
4.76 (dt, J = 47.6, 4.9 Hz, 2 H), 4.20 (dt, J = 25.6, 4.9 Hz, 2
H). 19C NMR: d = 170.94, 144.08, 135.80, 129.94, 129.31 (2
C), 128.90 (2 C), 127.89 (2 C), 127.83 (2 C), 126.91, 81.52
(d, J = 168.7 Hz), 51.57 (d, J = 20.7 Hz). 19F NMR: d = –
222.60 to –222.98 (m, 1 F). HRMS (EI): m/z calcd for
C15H14NOF: 243.1059; found: 243.1057.
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(S)-1-Fluoro-2-aminopropane Hydrochloride (S)-
(5)·HCl: White solid; mp 123–124 °C (lit.4e 127–127.5 °C);
[a]D21 +12.4 (c 1.01, MeOH) {lit.4e [a]D23 +12.7 (c 1.01,
MeOH)}. (R)-MTPA amide of (S)-5 19F NMR: d = –69.54 (s,
3 F), –232.36 (dt, J = 26.2, 47.0 Hz, 1 F).
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(R)-1-Fluoro-2-aminopropane Hydrochloride (R)-
(5)·HCl: White solid; mp 123–124.5 °C (lit.4e 127–128 °C);
[a]D22 –13.7 (c 1.00, MeOH) {lit.4e [a]D 23 –14.9 (c 1.10,
MeOH)}. (R)-MTPA amide of (R)-5; 19F NMR: d = –69.47
(s, 3 F), –232.73 (dt, J = 26.2, 47.0 Hz, 1 F).
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Synlett 2006, No. 11, 1744–1746 © Thieme Stuttgart · New York