Synthesis of C6F5-substituted aminoethanols via acetate ion mediated C6F5-group transfer reaction

Article abstract of DOI:10.1055/s-2006-926278

A new approach for the synthesis of N-(pentafluorophenylmethyl) aminoethanols is developed. The method includes alkylation of imines with 2-tris(pentafluorophenyl)silyloxyethyl inflate, prepared from ethylene oxide and (C₆F₅)₃

Full text of DOI:10.1055/s-2006-926278

PAPER
489
Synthesis of C6F5-Substituted Aminoethanols via Acetate Ion Mediated
C6F5-Group Transfer Reaction
Synthesis of
C
F
-
6 5iSubstit
t
ute
d
A
m
a
inoethano
l
ls ij V. Levin,a Alexander D. Dilman,*a Pavel A. Belyakov,a Alexander A. Korlyukov,b Marina I. Struchkova,a
Mikhail Y. Antipin,b Vladimir A. Tartakovskya
a
N. D. Zelinsky Institute of Organic Chemistry, Leninsky Prosp. 47, 119991 Moscow, Russian Federation
Fax +7(95)1355328; E-mail: adil25@mail.ru
A. N. Nesmeyanov Institute of Organoelement Compounds, Vavilov Str. 28, 119991 Moscow, Russian Federation
b
Received 15 June 2005; revised 24 August 2005
We have recently reported a method for the synthesis of
(pentafluorophenylmethyl)amines via a three-component
silicon Mannich reaction [Scheme 1, (a)].6 However, ap-
plication of this protocol to the coupling of benzaldehyde
Abstract: A new approach for the synthesis of N-(pentafluorophen-
ylmethyl)aminoethanols is developed. The method includes alkyl-
ation of imines with 2-tris(pentafluorophenyl)silyloxyethyl triflate,
prepared from ethylene oxide and (C6F5)3SiOTf, to give 2-silyloxy-
ethyliminium ions. Their treatment with sodium acetate induces C– and N-methylethanolamine afforded the desired product
in only 28% yield after a reaction time of 67 hours.6 In this
C bond formation proceeding as transfer of the C6F5 group from the
five-coordinate silicate intermediate to the iminium center.
paper we describe a more efficient approach to aminoal-
Key words: silicon, hypercoordination, amino alcohols, imines,
tris(pentafluorophenyl)silyl derivatives
cohols 1 based on the coupling of imines, ethylene oxide,
and tris(pentafluorophenyl)silyltriflate as a source of C6F5
group [Scheme 1, (b)]. The key steps of the process in-
volve the formation of silyloxyethyliminium salts and
b-Aminoalcohols constitute an important class of organic Lewis base mediated transfer of the pentafluorophenyl
compounds. They have found wide utilization in asym- group from the silicon to the iminium carbon atom.
metric synthesis as chiral auxiliaries and ligands.1 Anoth-
Addition of ethylene oxide to the mixture of N-methyl-C-
er significant area of applications of b-aminoalcohols is
associated with their diverse biological activity.2 At the
same time it is known that the presence of a fluorinated
substituent at the a-position of the nitrogen atom of
amines, i.e. as in the fragment Rf–CR2–NR2, also may pro-
vide derivatives displaying interesting pharmacological
properties3 and the latter phenomenon has stimulated the
intense investigations directed towards synthesis of fluor-
inated amines.4 As a consequence, fluorinated b-aminoal-
cohols, containing two adjacent pharmacophore fragments,
have become attractive targets.5 Herein we present our
studies towards a sub-class of fluorinated b-aminoalco-
hols, namely N-(pentafluorophenylmethyl)aminoethanols
1.
phenylimine (2a) and (C6F5)3SiOTf7 in dichloromethane
at room temperature cleanly gave iminium salt 3a
(Scheme 2). However this procedure cannot be applied to
enolizable imines, since the latter are incompatible with
silyl triflate. Thus, when N-methyl-C-isopropylimine (2b)
was mixed with (C6F5)3SiOTf in CDCl3, the N-silylena-
mine and protonated imine were immediately observed by
NMR spectroscopy, suggesting that the silyl group is first
transferred from (C6F5)3SiOTf onto 2b followed by depro-
tonation of silyliminium cation by another molecule of
2b8 (Scheme 2).
To overcome the problem of imine silylation we decided
to introduce the silyloxyethyl group by means of direct
alkylation of the imine. For this purpose we synthesized 2-
R2
OH
R2
R1
OH
R1 = Ph, R2 = Me
r.t., 67 h, 28%
N
N
H
(a)
O
C6F5
Si C6F5
OMe
HO
C6F5
R1
ref. 6
R2
(C6F5)3SiOMe
OH
N
R1
C6F5
Lewis base
O
R2
R2
R1
OSi(C6F5)3
1
N
N
(b)
R1
OTf
(C6F5)3SiOTf
Scheme 1
SYNTHESIS 2006, No. 3, pp 0489–0495
x
x
.
x
x
.2
0
0
5
Advanced online publication: 11.01.2006
DOI: 10.1055/s-2006-926278; Art ID: T08205SS
© Georg Thieme Verlag Stuttgart · New York

490
V. V. Levin et al.
PAPER
tris(pentafluorophenyl)silyloxyethyl triflate 4 by the in- mation to give the final aminoethanol in a reasonable
teraction of (C6F5)3SiOTf with ethylene oxide in the pres- yield (vide infra). Imines derived from linear aldehydes,
ence of 5 mol% of pyridine9 (Equation 1). Surprisingly, e.g. N-butyl-C-ethylimine, gave complex mixtures that
triflate 4 turned out to be a quite stable solid (mp 63–66 may be tentatively rationalized by facile loss of a proton
°C), which can be recrystallized from hexane. This com- from silyloxyethyliminium cation at the rate comparable
pound can be conveniently handled under an argon atmo- to the rate of alkylation. Iminium salts derived from C-
sphere at room temperature, whereas cooling to –25 °C is arylimines 3 can be isolated in individual state and char-
preferable for long-term storage to prevent decomposi- acterized by 1H, 13C, and 19F NMR spectroscopy, as exem-
tion.
plified for 3a,c. For 3c the structure was established by X-
ray diffraction analysis (Figure 2) that demonstrated the
gauche conformation of silyloxy and iminium functional-
ities similar to that in 4. The configuration of C–N double
bond was established either by NOE experiments (for 3a,
E:Z = 8:1) or from X-ray data (for 3c, E). It is interesting
to note that substituents R1 and R2, being in trans orienta-
tion in starting imines 2a,c, are in cis arrangement in imi-
nium salts 3a,c. This phenomenon may be explained by
the C–N double bond isomerization, which takes place ei-
ther in starting imine prior to alkylation or in iminium cat-
ion.
O
Me
+
Me
Ph
OSi(C6F5)3
N
N
(C6F5)3SiOTf
Ph
OTf
2a
3a
Me
Me
Si(C6F5)3
OTf
N
N
Me
+
(C6F5)3SiOTf
Me
2b
Me
Me
Me
Si(C6F5)3
H
Me
N
N
2b
Me
Me
+
OTf
Me
Me
Scheme 2
5 mol% Py
O
OSi(C6F5)3
73%
(C6F5)3SiOTf
+
TfO
4
Equation 1
The crystal and molecular structure of 4 was studied by X-
ray diffraction analysis (Figure 1). Analysis of Cambridge
database reveals that compound 4 is the first example
where the OTf group is bound to an acyclic chain,10 while
published data include structures of aryl, vinyl, and carbo-
hydrate triflates.11 The O(2)–C(2) bond of 1.481 Å is close
to that in carbohydrate derivatives (1.46–1.49 Å), but
longer than in sp2 bound triflates (1.41–1.45 Å). Of spe-
cial note is the gauche arrangement of OTf and OSi(C6F5)3
Figure 1 The molecular structure of 4 presented in thermal ellip-
soids at 50% probability. Hydrogen atoms are omitted for clarity.
Selected bonds and angles (Å and °): Si(1)–O(1) 1.614(1), Si(1)–
substituents (torsion angle OCCO is equal to 74.6°, see C(11) 1.875(2), O(1)–C(1) 1.422(2), O(2)–C(2) 1.481(2), C(1)–C(2)
1.501(2); O(1)–Si(1)–C11 109.40(6)°, O(1)–C(1)–C(2)–O(2)
–74.59(17)°.
projection), which is characteristic for stereoelectronic in-
teractions between sC–H and s*C–X orbitals.12 It should be
also noted that in 4 the interatomic distance between O(2)
R2
OSi(C6F5)3
R2
R1
OSi(C6F5)3
of triflate group and C(16) of phenyl ring is equal to 2.956
Å, that is noticeably shorter than the sum of van der Waals
radii (3.33 Å). Possibly the high steric overcrowding in
molecule leads to weak nonbonding interactions between
alkyl triflate and pentafluorophenyl moieties.
TfO
N
N
4
R1
OTf
2
3a R1 = Ph, R2 = Me
b R1 = i-Pr, R2 = Me
c R1 = 2-furfuryl, R2 = Me
Triflate 4 smoothly reacted with imines 2 generating imi-
nium salts 3 (Equation 2). The alkylation of C-arylimines
was usually performed in refluxing dichloroethane and
proceeded quite cleanly. The reaction of N-methyl-C-iso-
propylimine (2b) was carried out at room temperature for
16 hours furnishing salt 3b along with significant amounts
of by-products. Although isolation of pure 3b was prob-
lematic, it was successfully employed in further transfor-
Equation 2
The transformation of salts 3 into ethanolamines 1 relies
on the activation of silicon atom by a Lewis base to gen-
erate pentacoordinate silicate intermediate with subse-
quent intra- or intermolecular transfer of C6F5 group onto
Synthesis 2006, No. 3, 489–495 © Thieme Stuttgart · New York

PAPER
Synthesis of C6F5-Substituted Aminoethanols
491
iminium electrophile (Scheme 3). Using isolated salt 3a
as model substrate we performed the optimization of reac-
tion conditions for the synthesis of 1a (R1 = Ph, R2 = Me)
by varying the nucleophilic mediator (Table 1).
Table 1 Variation of Lewis Basic Mediator and Reaction Condi-
tionsa
Entry
Lewis base
Solvent
Yield of 1a
(%)b
1
2
3
4
5
6
7
Py-N-oxide
(Me2N)3PO
AcOH–Et3N
LiOAc
CDCl3–CD3CNc
CDCl3–CD3CNc
CH2Cl2
–
C6F5
R2
R1
OSi(C6F5)3
Lewis base
R2
R1
O
Si LB
N
–
N
C6F5
C6F5
OTf
75
79
87
89
94
3
R2
O
R2
OH
DMF
N
Si(C6F5)2
N
aq Na2CO3
LB
NaOAc
DMF
R1
C6F5
R1
C6F5
1
NaOAc
MeCN
Scheme 3
NaOAc
THF
a Conditions: r.t., 20 min; the ratio of reagents: 3a/Lewis base = 1:1.2.
b Isolated yield.
Pyridine-N-oxide and hexamethylphosphoric acid tri-
amide, which are known to be one of the strongest neutral
silicon specific Lewis bases,13 proved to be completely
unreactive coexisting with 3a with no signs of interaction
(Table 1, entries 1 and 2). In recent reports Mukaiyama
and co-workers demonstrated that lithium or tetrabutyl-
ammonium acetate in DMF effected trifluoromethylation
of carbonyl compounds and activated imines by
Me3SiCF3.14 We tested the Mukaiyama conditions for our
system and observed that acetate ion taken in any form
and in different solvents worked well for the transfer of
C6F5 group in salt 3a. Indeed, acetate ion either generated
in situ from acetic acid and triethylamine or added in the
form of lithium or sodium salt instantaneously initiated
the reaction, furnishing after desilylative workup fluori-
nated aminoalcohol 1a in high yield (Table 1, entries 3–
7). Employment of sodium acetate in tetrahydrofuran
seems to be the most practical, and this procedure was se-
lected for further investigations.15
c Reaction performed in a mixed solvent and monitored by 1H NMR.
The C–N bond formation occurs via alkylation of imines,
whereas the key step for the C–C bond formation includes
the activation of silicon with acetate ion, allowing for the
transfer of pentaflurophenyl group from pentacoordinate
silicate species onto iminium carbocation.
Under the optimized conditions a series of imines was em-
ployed in acetate ion mediated synthesis of N-(pentafluo-
rophenylmethyl)aminoethanols 1. Table 2 lists the
conditions for the generation of silyloxyethyliminium
ions 3, which were used without isolation. Their treatment
with sodium acetate uniformly required 20 minutes at
room temperature. Imines containing at the carbon atom
electron-donating and electron-withdrawing substituents,
tert-butyl and a-branched alkyl groups, gave good yields
of products.
As obvious from these results, the transfer of C6F5 group
leading to C–C bond formation was cleanly performed un-
der standard conditions, and is expected to pose no prob-
lems when applied to different silyloxyiminium salts 3.
On the other hand, the synthesis of salts 3 involving C–N Figure 2 The molecular structure of 3c presented in thermal ellip-
soids at 50% probability. Hydrogen atoms and triflate anion are omit-
ted for clarity. Selected bonds and angles (Å and °): Si(1)–O(1)
1.615(2), C(1)–C(2) 1.498(4), O(1)–C(1) 1.414(3), N(1)–C(2)
1.489(4), N(1)–C(3)–C(4) 130.0(3)°, O(1)–C(1)–C(2)–N(1)
bond formation is more sensitive and substrate-dependent
process, and, in fact, availability of salts 3 defines the
scope of the present methodology.
–64.8(4)°.
In summary, a convenient approach for the preparation of
N-(pentafluorophenylmethyl)aminoethanols based on
coupling of imines with silyloxyethyl triflate derived from
ethylene oxide and (C6F5)3SiOTf, has been developed.
Synthesis 2006, No. 3, 489–495 © Thieme Stuttgart · New York

492
V. V. Levin et al.
PAPER
Table 2 Synthesis of Aminoalcohols 1a
R2
R2
OH
1. 4, ClCH2CH2Cl, ∆
2. NaOAc, THF, 20 min
N
N
R1
R1
C6F5
2
1
Entry
1
2
R1
Ph
R2
1
Time (h)b
Yield of 1 (%)c
2a
2b
2c
2d
2e
2f
2g
2h
2i
Me
1a
1b
1c
1d
1e
1f
1g
1h
1i
0.5
16
0.5
1
78
56
86
85
66
73
67
74
80
72
78
67
2d
3e
4
i-Pr
a-furyl
Me
Me
p-MeOC6H4
t-Bu
Bn
5
Bn
2
6
p-ClC6H4
p-NO2C6H4
Ph
n-Bu
2
7
Me
3
8
Ph
5
9
a-thienyl
a-furyl
p-MeOC6H4
1
10
11
12
2j
2k
2l
Ph
Ph
Bn
1j
1k
1l
0.5
3
E-PhCH=CH
c-C5H9
1
a The ratio of reagents: 2/4/NaOAc = 1:1.05:1.2.
b Time for the interaction of 2 with 4 to give iminium salt 3.
c Isolated yield.
d Interaction of 2 with 4 was performed in CH2Cl2 at r.t.
e Interaction of 2 with 4 was performed in THF at r.t.
13C NMR (50 MHz, CDCl3): d = 62.9, 75.6, 104.1 (tm, J = 27 Hz),
118.6 (q, J = 319.4 Hz), 137.6 (dm, J = 255.5 Hz), 144.2 (dm, J =
259.8 Hz), 149.3 (dm, J = 247.0 Hz).
19F NMR (188 MHz, CDCl3): d = –160.34 (m, meta), –146.71 (tt,
J = 5.1, 19.4 Hz, para), –128.81 (m, ortho), –76.10 (s, CF3).
All reactions were performed under an argon atmosphere. Dichlo-
romethane and dichloroethane were distilled from CaH2 prior to
use. Acetonitrile was distilled from CaH2 and stored over MS 4 Å.
Column chromatography was carried out employing Merck silica
gel (Kieselgel 60, 230–400 mesh). Precoated silica gel plates F 254
were used for TLC; visualizing with UV and/or acidic aq KMnO4
solution. 1H NMR, 13C NMR and 19F NMR spectra were obtained
on Bruker AM-300, WM-250, or AC-200 spectrometers. Mi-
croanalyses were performed on a Karlo Erba 1106 instrument.
Impurities
1H NMR (200 MHz, CDCl3): d = 3.70 (t, J = 4.5 Hz), 3.77 (t, J = 4.3
Hz), 4.06 (t, J = 4.1 Hz), 4.53 (t, J = 4.5 Hz).
2-Tris(pentafluorophenyl)silyloxyethyl Triflate (4)
N-Methyl-N-[2-tris(pentafluorophenyl)silyloxyethyl]-C-phen-
yliminium Triflate (3a)
Pyridine (31 mL, 0.38 mmol) and ethylene oxide (0.47 mL, 9.41
mmol) were successively added to a suspension of silyltriflate (5.11
g, 7.53 mmol) in CH2Cl2 (10 mL) at 0 °C. After 10 min at 0 °C the
cooling bath was removed, the mixture was stirred for an additional
20 min at r.t., and the solvent was evaporated under vacuum. Hex-
ane (20 mL) was added, and the mixture was heated up to reflux and
filtered through glass wool while hot, the residue was washed with
hexane (2 × 5 mL) at r.t. The combined hexane phase was warmed
to obtain a clear solution and left in the freezer (–23 °C) overnight.
The cold solvent was decanted, the solid was washed with hexane
(5 mL), and dried under vacuum to afford 4 (4.51 g) that corre-
Imine 2a (68 mg, 0.571 mmol) was added to a suspension of triflate
4 (433 mg, 0.6 mmol) in DCE (1 mL) at r.t. The mixture was re-
fluxed for 30 min followed by cooling to 0 °C that caused formation
of the precipitate. The solvent was decanted, the resulting powder
was washed with DCE–hexane (1:2, 2 × 0.5 mL), and dried under
vacuum to give 3a (312 mg, 65%); mp 171–173 °C.
E Isomer
1H NMR (250 MHz, CDCl3–CD3CN, 4:1): d = 3.68 (s, 3 H, NCH3),
4.14–4.27 [m, 4 H, (CH2)2], 7.47–7.59 (m, 2 H, CHPh), 7.62–7.79
(m, 3 H, CHPh), 8.82 (s, 1 H, =CH). In the major isomer an NOE be-
tween the CH=N and (CH2)2 protons was observed.
1
sponds to 83% yield. However, according to H NMR the product
contains ca. 10 mol% of unidentified impurities. Further purifica-
tion of this material failed. The single crystals for X-ray analysis16
were grown by recrystallization from large amount of hexane at 5
°C; mp 63–66 °C.
1H NMR (200 MHz, CDCl3): d = 4.26 (t, J = 4.1 Hz, 2 H), 4.64 (t,
J = 4.1 Hz, 2 H).
13C NMR (50 MHz, CDCl3–CD3CN, 4:1): d = 41.7, 60.7, 64.7,
103.6 (tm, J = 27.4 Hz), 129.2, 132.5, 136.0, 137.5 (dm, J = 254.0
Hz), 144.0 (dm, J = 259.4 Hz), 149.0 (dm, J = 246.8 Hz), 173.0.
Synthesis 2006, No. 3, 489–495 © Thieme Stuttgart · New York

PAPER
Synthesis of C6F5-Substituted Aminoethanols
493
19F NMR (188 MHz, CDCl3–CD3CN, 4:1): d = –161.12 (m, meta),
–147.73 (tt, J = 5.6, 18.8 Hz, para), –129.34 (dm, J = 20.8 Hz,
ortho), –80.18 (s, CF3).
1H NMR (250 MHz, CDCl3): d = 0.73 (d, J = 6.6 Hz, 3 H, Me), 1.13
(d, J = 6.6 Hz, 3 H, Me), 2.15 (t, J = 2.6 Hz, 3 H, NCH3), 2.32–2.61
(m, 4 H, OH + Me2CH + NCH2), 3.51–3.63 (m, 2 H, CH2O), 3.67
(d, J = 11.2 Hz, 1 H, CHN).
Z Isomer
13C NMR (50 MHz, CDCl3): d = 20.4, 21.0, 27.6 (t, J = 3.2 Hz), 36.0
(t, J = 1.7 Hz), 55.4, 58.0, 67.1 (t, J = 2.9 Hz), 110.6 (tm, J = 18.9
Hz), 137.5 (dm, J = 252.0 Hz), 139.9 (dm, J = 253.4 Hz), 145.2 (dm,
J = 244.9 Hz).
1H NMR (250 MHz, CDCl3–CD3CN, 4:1): d = 8.99 (s, 1 H, =CH).
13C NMR (50 MHz, CDCl3–CD3CN, 4:1): d = 47.8, 55.2, 60.3,
174.5.
19F NMR (188 MHz, CDCl3–CD3CN, 4:1): d = –147.56 (tt, J = 5.6,
19.4 Hz, para).
19F NMR (188 MHz, CDCl3): d = –162.56 (m, meta), –156.05 (t,
J = 20.8 Hz, para), –138.58 (br Dn1/2 = 429.5 Hz, ortho).
Anal. Calcd for C29H13F18NO4SSi: C, 41.39; H, 1.56; N, 1.66.
Found: C, 41.28; H, 1.54; N, 1.64.
Anal. Calcd for C13H16F5NO: C, 52.53; H, 5.43; N, 4.71. Found: C,
52.47; H, 5.49; N, 4.74.
N-Methyl-N-[2-tris(pentafluorophenyl)silyloxyethyl]-C-(fur-
furyliminium Triflate (3c)
( )-N-(Furyl-2-pentafluorophenylmethyl)-N-methyl-2-amino-
ethanol (1c)
Yield: 262 mg (86%); oil; Rf 0.22 (hexanes–EtOAc, 2:1).
1H NMR (250 MHz, CDCl3): d = 2.30 (s, 3 H, NCH3), 2.50–2.77 (m,
3 H, NCH2 + OH), 3.54–3.69 (m, 2 H, OCH2), 5.32 (m, 1 H, CH),
6.37 (m, 2 H, 2CHAr), 7.35 (s, 1 H, CHAr).
13C NMR (63 MHz, CDCl3): d = 38.4, 55.6, 58.2, 58.3, 108.3, 110.5,
111.6 (tm, J = 17.1 Hz), 137.6 (dm, J = 254.0 Hz), 140.7 (dm, J =
254.9 Hz), 142.2, 145.4 (dm, J = 254.0 Hz), 151.0.
Imine 2c (68 mg, 0.571 mmol) was added to a suspension of triflate
4 (467 mg, 0.649 mmol) in DCE (1 mL) at r.t. After stirring for 30
min the mixture was cooled to 0 °C that caused formation of the pre-
cipitate. The solvent was decanted, the resulting powder was
washed with DCE (2 × 0.5 mL), and dried under vacuum to give 3c
(318 mg, 67% yield). The single crystals for X-ray analysis were
grown by recrystallization from DCE–MeCN; mp 173–175 °C (de-
comp).
19F NMR (188 MHz, CDCl3): d = –162.31 (m, meta), –155.06 (t,
J = 20.8 Hz, para), –139.78 (m, ortho).
1H NMR (200 MHz, CDCl3–CD3CN, 4:1): d = 3.71 (s, 3 H, NCH3),
4.05 (t, J = 4.6 Hz, 2 H, CH2) 4.17 (t, J = 4.6 Hz, 2 H, CH2), 6.79
(dd, J = 1.6, 3.9 Hz, 1 H, CHAr), 7.80 (d, J = 3.9 Hz, 1 H, CHAr), 8.07
(s, 1 H, CHAr), 8.51 (s, 1 H, CH).
Anal. Calcd for C14H12F5NO: C, 52.34; H, 3.77; N, 4.36. Found: C,
52.41; H, 4.79; N, 4.31.
13C NMR (50 MHz, CDCl3–CD3CN, 4:1): d = 41.2, 61.2, 63.5,
103.2 (tm, J = 24.1 Hz), 115.2, 135.6, 137.0 (dm, J = 252.7 Hz),
143.6 (dm, J = 258.3 Hz), 148.6 (dm, J = 244.1 Hz), 153.5, 154.7.
19F NMR (188 MHz, CDCl3–CD3CN, 4:1): d = –160.93 (m, meta),
–147.51 (tt, J = 5.6, 20.1 Hz, para), –129.83 (dm, J = 19.4 Hz,
ortho), –80.20 (s, CF3).
( )-N-Benzyl-N-(4-methoxyphenylpentafluorophenylmethyl)-
2-aminoethanol (1d)
Yield: 353 mg (85%); oil; Rf 0.30 (hexanes–EtOAc, 3:1).
1H NMR (300 MHz, CDCl3): d = 2.22 (s, 1 H, OH), 2.61–2.72 (m,
1 H, NCHAHBCH2), 2.82–2.94 (m, 1 H, NCHAHBCH2), 3.49–3.69
(m, 2 H, OCH2), 3.62 (d, J = 14.0 Hz, 1 H, PhCHAHB), 3.82 (s, 3 H,
OMe), 3.94 (d, J = 14.0 Hz, 1 H, PhCHAHB), 5.51 (s, 1 H, CH), 6.92
(d, J = 8.8 Hz, 2 H, CHAr), 7.24–7.40 (m, 5 H, Ph), 7.45 (d, J = 8.8
Hz, 2 H, CHAr).
13C NMR (50 MHz, CDCl3): d = 52.5, 55.1, 55.8, 59.4, 61.1, 114.0,
114.4 (tm, J = 17.0 Hz), 127.2, 128.4, 128.6, 130.9, 137.7 (dm, J =
254.1 Hz), 138.6, 140.2 (dm, J = 254.1 Hz), 145.0 (dm, J = 249.1
Hz), 159.1.
Anal. Calcd for C27H11F18NO5SSi: C, 39.00; H, 1.33; N, 1.68.
Found: C, 38.79; H, 1.29; N, 1.71.
Synthesis of Ethanolamines 1; General Procedure
Imine 2a,d–l (0.95 mmol) was added to a suspension of triflate 4
(722 mg, 1 mmol) in DCE (1.8 mL) at r.t. The resulting mixture was
refluxed for a time indicated in Table 2 and evaporated under vacu-
um to give crude 3a,d–l. To the residue THF (2 mL) and powdered
NaOAc (93 mg, 1.14 mmol) were successively added, the mixture
was stirred for 20 min, cooled with ice/water bath, and quenched
with sat. aq Na2CO3 (0.2 mL). After stirring for several minutes at
r.t. the mixture was diluted with hexane–EtOAc (10 mL, 3:1), fil-
tered through Na2SO4, concentrated and chromatographed on silica
gel.
19F NMR (188 MHz, CDCl3): d = –162.23 (m, meta), –155.86 (t,
J = 20.8 Hz, para), –138.59 (m, ortho).
Anal. Calcd for C23H20F5NO2: C, 63.16; H, 4.61; N, 3.20. Found: C,
63.10; H, 4.68; N, 3.23.
( )-N-Benzyl-N-(2,2-dimethyl-1-pentafluorophenylpropyl)-2-
aminoethanol (1e)
Yield: 243 mg (66%); oil; Rf 0.42 (hexanes–EtOAc, 3:1).
The interaction of imine 2b with 4 was performed in CH2Cl2 at r.t.
for 16 h, followed by concentration in vacuum. Subsequent treat-
ment of 3b was carried out in THF according to the general proce-
dure.
1H NMR (200 MHz, CDCl3): d = 1.09 [s, 9 H, C(CH3)3], 2.13–2.37
(m, 2 H, NCHAHBCH2 + OH), 2.94 (ddd, J = 5.4, 8.8, 14.2 Hz, 1 H,
NCHAHBCH2), 3.07 (ddd, J = 1.9, 2.5, 13.8 Hz, 1 H, PhCHAHB),
3.54 (ddd, J = 2.8, 5.5, 11.2 Hz, 1 H, OCHAHB), 3.77 (ddd, J = 4.0,
9.8, 11.2 Hz, 1 H, OCHAHB), 4.15 (d, J = 14.1 Hz, 1 H, PhCHAHB),
4.20 (s, 1 H, CH), 7.22–7.41 (m, 5 H, Ph).
13C NMR (50 MHz, CDCl3): d = 29.2 (d, J = 4.3 Hz), 35.9, 53.8 (d,
J = 4.3 Hz), 56.6 (d, J = 5.7 Hz), 59.5 (d, J = 1.4 Hz), 64.8 (d, J =
4.3 Hz), 111.0 (tm, J = 22.8 Hz), 127.4, 128.5, 128.7, 139.2 (d, J =
2.8 Hz).
The interaction of 2c with 4 was performed in THF at r.t. for 30 min
followed by the addition of NaOAc. Subsequent workup was car-
ried out according to the general procedure.
( )-N-Methyl-N-(pentafluorophenylphenylmethyl)-2-amino-
ethanol (1a)6
Yield: 245 mg (78%); oil; Rf 0.36 (hexanes–EtOAc, 3:1).
( )-N-Methyl-N-(2-methyl-1-pentafluorophenylpropyl)-2-ami-
noethanol (1b)
Yield: 158 mg (56%); oil; Rf 0.22 (hexanes–EtOAc, 4:1).
19F NMR (188 MHz, CDCl3): d = –162.84 (m, meta), –155.28 (t,
J = 20.8 Hz, para), –138.30 (dt, J = 6.8, 25.2 Hz, ortho), –127.32
(dm, J = 25.2 Hz, ortho).
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494
V. V. Levin et al.
PAPER
Anal. Calcd for C20H22F5NO: C, 62.01; H, 5.72; N, 3.62. Found: C,
61.92; H, 5.74; N, 3.61.
19F NMR (188 MHz, CDCl3): d = –162.43 (m, meta), –155.45 (t, J =
20.8 Hz, para), –139.39 (dm, J = 16.7 Hz, ortho).
Anal. Calcd for C20H16F5NO2S: C, 55.94; H, 3.76; N, 3.36. Found:
C, 56.00; H, 3.75; N, 3.23.
( )-N-Butyl-N-(4-chlorophenylpentafluorophenylmethyl)-2-
aminoethanol (1f)
Yield: 283 mg (73%); oil; Rf 0.32 (hexanes–EtOAc, 5:1).
( )-N-(Furyl-2-pentafluorophenylmethyl)-N-phenyl-2-amino-
ethanol (1j)
Yield: 262 mg (72); oil; Rf 0.25 (hexanes–EtOAc, 3:1).
1H NMR (250 MHz, CDCl3): d = 0.87 (t, J = 7.2 Hz, 3 H, CH3),
1.17–1.36 (m, 2 H, CH2CH3), 1.50 (quint, J = 7.4 Hz, 2 H,
NCH2CH2), 2.20–2.62 (m, 3 H, NCH2 + OH), 2.65–2.91 (m, 2 H,
NCH2), 3.51–3.75 (m, 2 H, CH2O), 5.49 (s, 1 H, CH), 7.23 (d, J =
8.5 Hz, 2 H, CHAr), 7.37 (d, J = 8.5 Hz, 2 H, CHAr).
13C NMR (50 MHz, CDCl3): d = 13.8, 20.4, 28.6, 50.1, 51.9, 59.2,
60.2, 113.6 (tm, J = 16.3 Hz), 128.6, 128.8, 133.4, 137.7 (dm, J =
254.8 Hz), 137.8, 140.4 (dm, J = 246.3 Hz), 145.2 (dm, J = 244.1
Hz).
1H NMR (250 MHz, CDCl3): d = 2.01 (br s, 1 H, OH), 3.40–3.60
[m, 4 H, (CH2)2], 6.31–6.44 (m, 3 H, 2 × CHAr + CHN), 6.87–7.02
(m, 3 H, CHAr), 7.23 (t, J = 7.9 Hz, 2 H, CHAr), 7.45 (s, 1 H, CHAr).
13C NMR (50 MHz, CDCl3): d = 50.2 (t, J = 2.8 Hz), 54.6, 59.6,
109.9, 110.8, 112.8 (tm, J = 17.3 Hz), 117.5, 120.9, 129.4, 137.6
(dm, J = 254.1 Hz), 140.7 (dm, J = 254.8 Hz), 142.9, 145.0 (dm, J =
250.5 Hz), 146.9, 150.0.
19F NMR (188 MHz, CDCl3): d = –161.85 (m, meta), –155.14 (t,
J = 20.8 Hz, para), –138.65 (dm, J = 16.7 Hz, ortho).
19F NMR (188 MHz, CDCl3): d = –162.27 (m, meta), –155.02 (t, J =
20.8 Hz, para), –141.63 (m, ortho).
Anal. Calcd for C19H19ClF5NO: C, 55.96; H, 4.70; N, 3.43. Found:
C, 55.84; H, 4.61; N, 3.31.
Anal. Calcd for C19H14F5NO2: C, 59.53; H, 3.68; N, 3.65. Found: C,
59.41; H, 3.64; N, 3.61.
( )-N-Methyl-N-(4-nitrophenylpentafluorophenylmethyl)-2-
aminoethanol (1g)
Yield: 240 mg (67%); oil; Rf 0.26 (hexanes–EtOAc, 3:2).
1H NMR (250 MHz, CDCl3): d = 2.28 (s, 3 H, NCH3), 2.60 (t, J =
5.6 Hz, 2 H, NCH2), 3.71 (t, J = 5.5 Hz, 2 H, OCH2), 5. 31 (s, 1 H,
CH), 7.63 (d, J = 8.5 Hz, 2 H, CHAr), 8.15 (d, J = 8.8 Hz, 2 H, CHAr).
13C NMR (63 MHz, CDCl3): d = 38.7, 56.3, 58.7, 63.6, 112.3 (tm,
J = 14.7 Hz), 123.8, 127.9, 137.8 (dm, J = 254.0 Hz), 140.8 (dm, J =
255.8 Hz), 144.9 (dm, J = 252.2 Hz), 146.6, 147.2.
( )-N-(1-Pentafluorophenyl-3-phenylallyl)-N-phenyl-2-amino-
ethanol (1k)
Yield: 311 mg (78%); oil; Rf 0.31 (hexanes–EtOAc, 3:1). Upon
flash chromatography 0.5% of Et3N was added to the eluent. The
chromatographed product was > 98% pure, containing only traces
of Et3N and solvents. This compound is prone to decomposition on
storage at r.t.
1H NMR (250 MHz, CDCl3): d = 2.35 (br s, 1 H, OH), 3.38–3.71
[m, 4 H, (CH2)2], 5.70 (d, J = 4.0 Hz, 1 H, CHN), 6.60–6.70 (m, 2
H, CH=CH), 6.96–7.49 (m, 10 H, 2 × Ph).
13C NMR (50 MHz, CDCl3): d = 51.7, 59.5, 60.2, 114.9 (tm, J =
14.2 Hz), 120.7, 122.6, 126.0, 126.6, 128.3, 128.6, 129.3, 133.9,
135.9, 137.5 (dm, J = 253.4 Hz), 140.3 (dm, J = 242.0 Hz), 144.9
(dm, J = 251.9 Hz), 147.4.
19F NMR (188 MHz, CDCl3): d = –161.42 (m, meta), –154.16 (t, J =
20.8 Hz, para), –138.73 (dm, J = 16.7 Hz, ortho).
Anal. Calcd for C16H13F5N2O3: C, 51.07; H, 3.48; N, 7.44. Found:
C, 51.09; H, 3.61; N, 7.33.
( )-N-(Pentafluorophenylphenylmethyl)-N-phenyl-2-amino-
ethanol (1h)
19F NMR (188 MHz, CDCl3): d = –162.51 (m, meta), –155.74(t, J =
20.8 Hz, para), –141.97 (dd, J = 5.6, 22.2 Hz, ortho).
Yield: 277 mg (74%); oil; Rf 0.27 (hexanes–EtOAc, 3:1).
( )-N-Benzyl-N-(cyclopentylpentafluorophenylmethyl)-2-ami-
noethanol (1l)
Yield: 263 mg (67%); oil; Rf 0.30 (hexanes–EtOAc, 5:1).
1H NMR (200 MHz, CDCl3): d = 1.86 (s, 1 H, OH), 3.34–3.56 [m,
4 H, (CH2)2], 6.35 (s, 1 H, CH), 6.90–7.11 (m, 3 H, CHPh), 7.23–
7.49 (m, 7 H, CHPh).
1H NMR (200 MHz, CDCl3): d = 0.80–1.05 (m, 1 H, C5H9), 1.35–
1.78 (m, 6 H, C5H9), 2.09–2.41 (m, 3 H, C5H9 + OH), 2.81–3.02 (m,
2 H, CH2N), 3.10 (dt, J = 2.2, 13.7 Hz, 1 H, PhCHAHB), 3.39–3.53
(m, 1 H, OCHAHB), 3.71 (td, J = 3.4, 10.5 Hz, 1 H, OCHAHB), 4.01
(d, J = 11.7 Hz, 1 H, CHN), 4.09 (d, J = 13.7 Hz, 1 H, PhCHAHB),
7.25–7.39 (m, 5 H, Ph).
13C NMR (50 MHz, CDCl3): d = 25.1, 25.1, 30.8, 32.1, 40.0 (t,
J = 2.7 Hz), 51.4, 54.4, 58.7, 62.0, 111.8 (tm, J = 19.0 Hz), 127.3,
128.5, 128.7, 137.5 (dm, J = 252.0 Hz), 139.1, 140.0 (dm, J = 253.4
Hz), 145.5 (dm, J = 242.7 Hz).
13C NMR (50 MHz, CDCl3): d = 51.2 (t, J = 2.3 Hz), 59.8, 60.7,
114.9 (tm, J = 14.2 Hz), 118.4, 121.4, 128.0, 128.1, 128.9, 129.3,
137.6 (dm, J = 253.4 Hz), 138.1, 140.4 (dm, J = 254.8 Hz), 144.9
(dm, J = 245.6 Hz), 147.8.
19F NMR (188 MHz, CDCl3): d = –162.31 (m, meta), –155.50 (t, J =
20.8 Hz, para), –140.58 (m, ortho).
Anal. Calcd for C21H16F5NO: C, 64.12; H, 4.10; N, 3.56. Found: C,
64.21; H, 4.02; N, 3.56.
( )-N-(4-Methoxyphenyl)-N-(pentafluorophenylthiophenyl-2-
methyl)-2-aminoethanol (1i)
Yield: 326 mg (80%); oil; Rf 0.31 (hexanes–EtOAc, 3:1).
1H NMR (200 MHz, CDCl3): d = 2.38 (t, J = 5.6 Hz, 1 H, OH),
3.04–3.35 (m, 2 H, NCH2), 3.39–3.52 (m, 2 H, OCH2), 3.76 (s, 3 H,
OMe), 6.16 (s, 1 H, CHN), 6.80 (d, J = 8.8 Hz, 2 H, 2 × CHAr), 6.96
(dd, J = 3.7, 5.1 Hz, 1 H, CHthienyl), 7.06–7.10 (m, 1 H, CHthienyl),
7.13 (d, J = 8.8 Hz, 2 H, 2 × CHAr), 7.30 (dd, J = 1.2, 5.1 Hz, 1 H,
CHthienyl).
19F NMR (188 MHz, CDCl3): d = –162.11 (m, meta), –155.53 (t, J =
21.5 Hz, para), –139.38 (br Dn1/2 = 69.1 Hz, ortho), –136.62 (br
Dn1/2 = 67.7 Hz, ortho).
Anal. Calcd for C21H22F5NO2: C, 63.15; H, 5.55; N, 3.51. Found: C,
63.11; H, 5.41; N, 3.51.
Acknowledgment
This work was supported by INTAS (project # 2003-55-1185). We
also thank Prof. S. L. Ioffe for start-up funding.
13C NMR (50 MHz, CDCl3): d = 53.6, 55.2, 59.4, 59.7, 114.4, 125.6,
125.9, 126.6, 126.7, 137.4 (dm, J = 253.4 Hz), 140.4 (dm, J = 254.1
Hz), 140.5, 142.6, 144.4 (dm, J = 254.1 Hz), 157.0.
Synthesis 2006, No. 3, 489–495 © Thieme Stuttgart · New York

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Synthesis of C6F5-Substituted Aminoethanols
495
(8) When N-methyl-C-phenylimine (2a) was combined with
(C6F5)3SiOTf in CDCl3 no silyl iminium ion was observed
(1H, 19F NMR control). Correspondingly, it is believed that
silyl iminium ion from 2b and (C6F5)3SiOTf is formed in
small equilibrium concentration.
(9) In the absence of pyridine lower yields of 4 were achieved,
presumably owing to oligomerization of ethylene oxide by
traces of triflic acid.
References
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(15) NaOAc is insoluble in THF. However, it dissolves in
reaction mixture as C6F5 group transfer occurs, thereby
allowing for convenient monitoring of reaction progress.
(16) Crystallographic data (excluding structure factors) have
been deposited with the Cambridge Crystallographic Data
Centre, CCDC 275041 (for 4) and 275042 (for 3c) and are
available free of charge at CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: +44 (1223)336033 or e-
mail: deposit@ccdc.cam.ca.uk].
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Synthesis 2006, No. 3, 489–495 © Thieme Stuttgart · New York