The synthesis of novel 4-(aminomethyl)oxazoline ligands

Article abstract of DOI:10.1055/s-2005-918477

A practical route to 2,3-bis(amino)-1-alcohols has been developed and utilized in the synthesis of a number of novel bis(oxazoline) ligands. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-918477

3446
PAPER
The Synthesis of Novel 4-(Aminomethyl)oxazoline Ligands
N
ovel 4-(A
e
minometh
r
yl)oxazo
a
line Ligand
i
s
me A. Griffith, Gareth J. Rowlands*
Department of Chemistry, University of Sussex, Falmer, Brighton, BN1 9QJ, UK
Fax +44(1273)677196; E-mail: g.rowlands@sussex.ac.uk
Received 9 September 2005
This paper is dedicated with respect to Professor Steven V. Ley on the occasion of his 60th birthday.
R1
Abstract: A practical route to 2,3-bis(amino)-1-alcohols has been
developed and utilized in the synthesis of a number of novel bis(ox-
azoline) ligands.
O
NBoc
O
O
R1
ii
i
OH
O
O
7a (94%)
7b (37%)
Key words: amines, amino alcohols, alkylations, ligands, asym-
metric catalysis
NBoc
NBoc
+
5
i-PrO
R1
NHBoc
6a R1 = morpholine (95%)
6b R1 = PhNH (89%)
6c R1 = 4-MeOC6H4NH (97%)
6d R1 = 3-NO2C6H4NH (68%)
The concept of bifunctional catalysis is inspired by the
mode of action of many enzymes, in that two reactive sites
within a molecule act in concert to bring about a desired
transformation.1 Previously, we reported an example of a
titanium–sulfoxide bifunctional catalyst.2 Ultimately,
whilst this complex produced a number of interesting re-
sults, it was not amenable to modification and optimiza-
tion. As a result we wanted to design a ligand scaffold that
was both simple to prepare and readily functionalized at a
late stage. In this paper we report our initial results on the
preparation of the 4-(aminomethyl)oxazoline moiety,
which has the potential to fulfill these criteria.
8a (0%)
8b (37%)
Scheme 2 Reagents and conditions: i. a) HOBt (1.1 equiv), EDCI
(1.1 equiv), amine R1 (1.1 equiv), DMF; b) Et3N, r.t., overnight; ii.
BH3·THF, THF, 0 °C to reflux, 3 h.
bis(amino) alcohols 2. The obvious precursor for these
densely functionalized molecules is the amino acid, serine
4.
Our initial strategy was based on the reductive amination
of Garner’s aldehyde7 but in our hands this reaction
proved unsatisfactory. Therefore, a two-step procedure in-
volving amide formation and reduction was investigated.
The known acid 58 was converted to amides 6a–d in ex-
cellent yields utilizing standard HOBt/EDCI coupling
conditions (Scheme 2), but the reduction to amine 7 was
far more problematic. The use of metal-based reducing
agents, such as LiAlH4 or DIBAL, gave highly capricious
results, with yields varying erratically from 11–70%, and
was deemed unsatisfactory. Believing that the problem
was the coordination of the metal and the bis(amino) alco-
hol, reduction with BH3·THF complex was attempted.9
Reduction of the morpholine amide 6a gave the protected
bis(amino) alcohol 7a in an excellent 94% yield. Unfortu-
nately, the reduction of the aniline derivative 6b resulted
in the formation of an inseparable 1:1 mixture of the de-
sired protected bis(amino) alcohol 7b and the isopropyl
ether 8b. Presumably, the secondary amine somehow fa-
cilitates activation of the Boc-protected amine and per-
mits the formation of an oxonium species that is reduced
to the ether. It was clear that the use of the fully protected
serine derivative 5 was going to thwart our attempts to de-
vise a general route to the bis(amino) alcohols.
HO
NHR1
O
O
O
NH2
N
N
HO
OH
2
NH2
serine 4
HN
R1
NH
R1
R2
R2
3a R2 = COX
3b R2 = CN
1
Scheme 1 The synthesis of bis[4-(aminomethyl)oxazolines].
Oxazolines have an exceptional pedigree as chiral
ligands3 and they offer an excellent framework for the de-
sign of novel ligands. Surprisingly, there are few exam-
ples of their modification after ring formation as a means
of increasing structural diversity.4,5 We were interested in
the bis[4-(aminomethyl)oxazolines] 1 (Scheme 1), as the
amine moiety would allow further elaboration of the cen-
tral core and has great potential in the formation of bifunc-
tional catalysts.6
Oxazolines are normally prepared by the condensation of
an amino alcohol and either a carboxylic acid derivative
3a or a nitrile 3b (Scheme 1). Therefore, the initial target
was to develop a general route to the deceptively simple
Whilst a plethora of protecting groups for the hydroxy
functionality exist,10 any one of which might be amenable
to the preparation of 2, their use is inefficient, adding extra
steps to the synthesis and reduces the practicality of any
synthesis. Consequently, a far more direct route avoiding
the unnecessary alcohol protection was explored. After
SYNTHESIS 2005, No. 19, pp 3446–3450
x
x.
x
x
.
2
0
0
5
Advanced online publication: 14.11.2005
DOI: 10.1055/s-2005-918477; Art ID: C07805SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Novel 4-(Aminomethyl)oxazoline Ligands
3447
O
O
An alternative route to the oxazoline skeleton is via the di-
rect condensation of a nitrile and an amino alcohol in the
presence of Cd(OAc)2.14 Heating the three bis(amino) al-
cohols 2a–c with dimethylmalononitrile 15 and Cd(OAc)2
in chlorobenzene to reflux gave the bis(oxazolines) 16a–
c in moderate yields (Scheme 6). It is conceivable that cy-
clization results in the formation of the novel bis[4-(hy-
droxymethyl)imidazoline] instead of the desired
bis(oxazoline). We believe that this is not the case prima-
rily due to the 13C NMR signal for C2 of the ring; in com-
pounds 16a–c this peak is above 170 ppm which appears
to be indicative of an oxazoline ring14,15 and not an imida-
zoline ring, in which this peak is normally closer to 160
ppm.16 At present we cannot rule out the possibility of
imidazoline formation.
Ar
ii, iii
i
HO
N
Ar
H
HO
OH
HO
N
NH2
H
NHBoc
NHBoc
9
10a Ar = Ph (81%)
2a (65%)
2b (72%)
2c (55%)
10b Ar = 4-MeOC6H4 (84%)
10c Ar = 3-CF3C6H4 (77%)
Scheme 3 Reagents and conditions: i. i-BuOCOCl, NMM, THF,
–15 to 0 °C, overnight; ii. BH3·THF, THF, reflux, 1 h; iii. TFA–H2O,
overnight.
extensive optimization it was found that N-Boc protected
serine 9 could be readily coupled to a range of substituted
anilines using iso-butyl chloroformate and N-methylmor-
pholine (NMM) under the conditions described by
Katritzky11 to give amides 10a–c in excellent yields
(Scheme 3). Direct reduction with BH3·THF complex and
subsequent treatment of the crude protected bis(amino) al-
cohol with TFA gave, after column chromatography, the
desired bis(amino) alcohols 2a–c in good yields.12 It was
vital that the reduction was stopped after 3 hours or reduc-
tion of the Boc group to N-methyl bis(amino) alcohol was
observed.
O
O
Ar
i
N
N
HO
N
+
H
NC
CN
NH2
HN
Ar
NH
Ar
2a–c
15
16a Ar = Ph (29%)
16b Ar = 4-MeOC6H4 (59%)
16c Ar = 3-CF3C6H4 (51%)
Et
Et
O
O
Scheme 6 Reagents and conditions: i. Cd(OAc)2·2H2O, PhCl,
reflux, overnight.
NH HN
TBDPSO
N
i
NH2
O
N
N
The five oxazoline ligands formed, 14a,b and 16a–c, have
shown highly intriguing preliminary results when used in
the catalytic addition of diethylzinc to benzaldehyde
(Scheme 7). Firstly, an N–H bond is vital for reactivity;
the reaction utilizing the morpholine substituted ligand
14a failed to furnish any product. All the other ligands
catalyzed alkylation. Secondly, the bis(oxazoline)
ligands, 16a–c, are generally superior to the mono(oxazo-
line) 14b in terms of activity; all the bis(oxazolines)
ligands double the yield of product formed. Mono(oxazo-
line) 14b gives poor results furnishing the benzylic alco-
hol 17 in poor yield and selectivity (40% yield; 24% ee).
This suggests that two zinc units must be coordinated
within close proximity and then act in unison to bring
about successful catalysis, which is in agreement with the
results of Reiser who has made a similar observation
when utilizing 4-(hydroxymethyl)oxazolines in the same
reaction.17 Thirdly, it is clear that the electronics of the
amine moiety make a significant difference to the catalyt-
ic activity and selectivity of the ligands.18 Not only does
the electron poor amine 16c produce a more reactive cat-
alyst, ligand 16c gives a 93% yield of 17 compared to only
72% of 17 when electron-rich 16b is used, but it is signif-
icantly more enantioselective as well, giving over double
the observed selectivity of electron rich amine 16b (54%
vs. 25%). It is interesting to speculate on the reasons for
these differences. The most common mechanism19 for the
addition of diethylzinc to aldehydes requires electron do-
nation from the ligand to activate one equivalent of dieth-
ylzinc, which would suggest the electron-rich ligand 16b
O
O
11
12
Scheme 4 Reagents and conditions: i. Et2C(COCl)2, Et3N, –10 °C
to r.t., overnight.
With a rapid, practical route to large quantities of the
bis(amino) alcohols 2 in hand we turned our attention to
oxazoline formation. The most reliable synthesis of the
oxazoline moiety is via N-acylation and subsequent cy-
clization. Unfortunately, selective acylation of the
bis(amino) alcohols was not possible; a mixture of N- and
O-acylation was observed. Interestingly, acylation of silyl
ether 11, made from 7a also failed, giving only the en-
amine 12, the product of silyl alcohol elimination
(Scheme 4). Even though the benzamides 13a and 13b
could be synthesized by a low yielding (<30%), convolut-
ed route and underwent smooth cyclization with DAST13
to give the mono(oxazolines) 14a,b in variable yields
(34–82%), the acylation strategy was abandoned as it was
judged to be impractical (Scheme 5).
Ph
O
R1
i
HO
N
NHBz
R1
13a R1 = morpholine
13b R1 = PhNH
14a R1 = morpholine (82%)
14b R1 = PhNH (34%)
Scheme 5 Reagents and conditions: i. DAST, K2CO3, CH2Cl2, –78
°C, 1 h.
Synthesis 2005, No. 19, 3446–3450 © Thieme Stuttgart · New York

3448
J. A. Griffith, G. J. Rowlands
PAPER
1H NMR (300 MHz, CDCl3): d = 8.85 (br s, 1 H, NH), 7.49 (d,
J = 8.1 Hz, 2 H, ArH), 7.32–7.27 (m, 2 H, ArH), 7.11 (t, J = 7.4 Hz,
1 H, ArH), 5.78 (d, J = 7.4 Hz, 1 H, NHBoc), 4.38–4.26 (m, 1 H, H-
3), 4.26–4.13 (m, 1 H, H-3), 3.85–3.66 (m, 1 H, H-2), 3.48–3.37 (br
s, 1 H, OH), 1.48 (s, 9 H, t-Bu).
13C NMR (75 MHz, CDCl3): d = 170.1, 137.8, 129.4, 125.1, 120.5,
81.4, 63.0, 55.7, 28.7.
should have made a better catalyst. The fact that the elec-
tron-poor ligand 16c gives a more reactive catalyst might
result from the increased Lewis acidity of the attached
zinc centre but this still does not explain the increased se-
lectivity. Clearly, more experimental evidence is required
before an accurate working model can be formulated.
MS (EI): m/z = 280 [M] +, 93, 57.
HRMS (EI): m/z calcd for C14H20N2O4Na [M + Na]+: 303.1315;
O
H
OH
Et
i
Ph
Ph
H
found: 303.1318.
17
(S)-tert-Butyl 3-Hydroxy-1-(4-methoxyphenylamino)-1-oxopro-
pan-2-ylcarbamate (10b)
ligand = 14a 0%; 0% ee
ligand = 14b 40%; 24% ee
ligand = 16a 83%; 45% ee
ligand = 16b 72%; 25% ee
ligand = 16c 93%; 54% ee
Yield: 20.20 g (84%); colorless solid; mp 107–110 °C; [a]D30 –95.9
(c 1.01, CHCl3).
IR (CHCl3): 3311, 2977, 2934, 2837, 1664, 1608, 1512, 1465, 1415,
1392, 1367, 1300, 1246, 1164, 1060, 1035 cm–1.
Scheme 7 Reagents and conditions: i. ZnEt2 (2.5 equiv), ligand (0.1
equiv), toluene, –78 °C.
1H NMR (300 MHz, CDCl3): d = 8.63 (br s, 1 H, NH), 7.32 (d,
J = 9.0 Hz, 2 H, ArH), 6.77 (d, J = 9.0 Hz, 2 H, ArH), 5.69 (br s, 1
H, NHBoc), 4.28–4.17 (m, 1 H, H-3), 4.17–4.05 (m, 1 H, H-3), 3.70
(s, 3 H, OMe), 3.70–3.57 (m, 1 H, H-2), 3.41–3.30 (br s, 1 H, OH),
1.40 (s, 9 H, t-Bu).
13C NMR (75 MHz, CDCl3): d = 169.9, 157.0, 130.8, 122.3, 114.5,
81.3, 63.1, 55.8, 55.6, 28.7.
In conclusion, we have developed a general, practical
route for the conversion of serine into valuable bis(amino)
alcohols and have used these in the preparation of a num-
ber of novel bis(oxazoline) ligands. The ligands show in-
teresting preliminary results in the addition of diethylzinc
to benzaldehyde. Moreover, the basic 4-(aminometh-
yl)oxazoline scaffold should be highly amenable to fur-
ther elaboration and we anticipate that derivatives of these
ligands will have potential in numerous other transforma-
tions.
MS (EI): m/z = 310 [M]+, 254, 123, 57.
HRMS (EI): m/z calcd for C15H22N2O5Na [M + Na]+: 333.1421;
found: 333.1421.
(S)-tert-Butyl 3-Hydroxy-1-oxo-1-(3-(trifluoromethyl)phenyl-
amino)propan-2-ylcarbamate (10c)
Yield: 16.20 g (77%); colorless solid; mp 92–95 °C; [a]D –77.1
(c 1.01, CHCl3).
26
1H and 13C NMR spectra were recorded on a Bruker Spectrospin
300 MHz spectrometer. IR spectra were recorded on a Perkin-Elmer
SpectrumOne FT-IR Spectrophotometer. MS were obtained using
VG Auto Spec Fisons Instruments and Bruker Daltonics Apex III.
Mps were measured on a Gallenkamp Melting Point Apparatus and
are uncorrected. Optical rotations were measured using a Perkin-
Elmer 241 Polarimeter. All reactions were carried out in oven-dried
flasks under a positive pressure of nitrogen. Chromatography refers
to flash column chromatography on Merck Kieselgel 60 (230–400
mesh). Petroleum ether used had a bp range 40–60 °C. N-(t-Bu-
tyl)carbonyl L-serine 9 was prepared according to the literature.20
IR (CHCl3): 3307, 3104, 2980, 2934, 1675, 1615, 1604, 1561, 1528,
1495, 1449, 1393, 1368, 1333, 1281, 1250, 1163, 1126, 1098, 1071
cm–1.
1H NMR (300 MHz, CDCl3): d = 9.06 (br s, 1 H, NH), 7.82 (s, 1 H,
ArH), 7.58 (d, J = 7.4 Hz, 1 H, ArH), 7.42–7.28 (m, 2 H, ArH),
5.83–5.69 (m, 1 H, NHBoc), 4.35–4.21 (m, 1 H, H-3), 4.21–4.10
(m, 1 H, H-3), 3.70 (br s, 1 H, OH), 3.25 (dd, J = 8.2, 4.5 Hz, 1 H,
H-2), 1.42 (s, 9 H, t-Bu).
13C NMR (75 MHz, CDCl3; 2 rotamers): d = 170.4, 157.3, 156.4,
138.4, 131.8 (q, J = 32.3 Hz, CCF3), 129.9, 126, 123.4, 122.3,
121.5, 121.5, 117.1, 117.1, 81.7, 63.1, 62.8, 60.8, 56.4, 55.8, 28.6,
21.5, 14.6.
Coupling of N-(tert-Butyl)carbonyl L-Serine 9 with Aniline
Derivatives; General Procedure
To a solution of N-(tert-butyl)carbonyl L-serine 9 (1.0 equiv) in
THF (0.3 M) at 0 °C was added N-methylmorpholine (1.1 equiv). A
solution of isobutyl chloroformate (1.1 equiv) in THF (2 M) was
added slowly over 15 min. After stirring the mixture for a further 15
min, the aniline derivative (1.2 equiv) was added in one portion and
the reaction was allowed to warm to r.t. overnight. The solvent was
removed under reduced pressure, the residue was dissolved in
EtOAc (150 mL), washed with sat. aq NaHCO3 (90 mL), HCl (1 N;
90 mL), and brine (100 mL). The organic layer was dried (MgSO4),
the solvent removed under reduced pressure, and the residue puri-
fied via column chromatography (SiO2; petroleum ether–EtOAc,
2:3).
MS (EI): m/z = 348 [M]+, 161, 104, 57.
HRMS (EI): m/z calcd for C15H20N2O4F3 [M + H]+: 349.1369;
found: 349.1357.
Amide Reduction and Deprotection; General Procedure
To a solution of amide 10 (1.0 equiv) in THF (0.1 M) at 0 °C was
slowly added a solution of BH3·THF complex (1 M in THF; 3.0
equiv). The mixture was heated to reflux for 1 h, then cooled in an
ice-bath, and carefully quenched by the addition of MeOH (5 mL
per mmol or until no reaction occurs). The solvent was removed un-
der reduced pressure, the residue was taken up in a mixture of TFA–
H2O (19:1; 150 mL) and stirred for 1.5 h. The solvent was removed
under reduced pressure, the residue dissolved in NaOH (2 M; 80
mL), and extracted with EtOAc (3 × 50 mL). The combined organic
layers were dried (MgSO4), concentrated under reduced pressure,
and purified by column chromatography (SiO2; CH2Cl2–MeOH–
33% NH4OH, 95:4.5:0.5).
(S)-tert-Butyl 3-Hydroxy-1-oxo-1-(phenylamino)propan-2-yl-
carbamate (10a)
Yield: 17.89 g (81%); colorless solid; mp 82–84 °C; [a]D –91.9
(c 1.04, CHCl3).
27
IR (CHCl3): 3310, 2977, 2931, 1671, 1600, 1537, 1499, 1445, 1392,
1367, 1298, 1163, 1060 cm–1.
Synthesis 2005, No. 19, 3446–3450 © Thieme Stuttgart · New York

PAPER
Novel 4-(Aminomethyl)oxazoline Ligands
3449
(R)-2-Amino-3-(phenylamino)propan-1-ol (2a)
Yield: 10.09 g (65%); white solid; mp 108–110 °C; [a]D +18.2
(c 1.03, CHCl3).
2,2-Bis{2-[(4R)-4-(phenylamino)methyl-1,3-oxazolinyl]}pro-
31
pane (16a)
Yield: 0.26 g (29%); pale yellow solid; mp 84–87 °C; [a]D30 +155
(c 0.99, CHCl3).
IR (Nujol): 1605, 1582, 1497, 1331, 1258, 1178, 1129, 1109, 1088,
1074, 1054, 1016 cm–1.
1H NMR (300 MHz, CD3OD): d = 7.29–7.13 (m, 2 H, ArH), 6.82–
6.69 (m, 3 H, ArH), 3.76 (dd, J = 10.9, 4.4 Hz, 1 H, H-1), 3.65 (dd,
J = 10.7, 5.4 Hz, 1 H, H-1), 3.35 (dd, J = 15.7, 8.3 Hz, 1 H, H-2),
3.21–3.12 (m, 2 H, H-3).
IR (Nujol): 3392, 2928, 1655, 1603, 1508, 1466, 1432, 1388, 1357,
1319, 1256, 1228, 1179, 1150, 1116, 1074, 972 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.08 (t, J = 8.4 Hz, 4 H, ArH),
6.63 (t, J = 7.3 Hz, 2 H, ArH), 6.54 (d, J = 7.8 Hz, 4 H, ArH), 4.50–
4.38 (m, 2 H, H-4), 4.31 (dd, J = 9.6, 8.1 Hz, 2 H, H-5), 4.14 (dd,
J = 7.9, 6.8 Hz, 2 H, H-5), 4.07 (br s, 2 H, 2 × NH), 3.26 (dd,
J = 12.3, 4.2 Hz, 2 H, H-1¢), 3.15 (dd, J = 12.2, 4.9 Hz, 2 H, H-1¢),
1.48 (s, 6 H, 2 × Me).
13C NMR (75 MHz, CDCl3): d = 171.1, 148.7, 129.6, 118, 113.5,
71.4, 65.8, 47.6, 39.4, 24.6.
MS (EI): m/z = 392 [M]+, 287, 182, 106 [M – PhNHCH2]+, 77.
HRMS (EI): m/z calcd for C23H28N4O2 [M + H]+: 393.2285; found:
13C NMR (75 MHz, CD3OD): d = 150.6, 130.4, 118.4, 114.3, 65.9,
53.5, 48.3.
MS (EI): m/z = 166 [M]+, 106 [M – CHNH2CH2OH]+, 77, 60 [M –
PhNHCH2]+.
HRMS (EI): m/z calcd for C9H15N2O [M + H]+: 167.1179; found:
167.1179.
(R)-2-Amino-3-(4-methoxyphenylamino)propan-1-ol (2b)
Yield: 8.57 g (72%); off-white solid; mp 84–87 °C; [a]D +14.8
(c 1.05, MeOH).
393.2265.
30
2,2-Bis{2-[(4R)-4-(4-methoxyphenylamino)methyl-1,3-oxazoli-
nyl]}propane (16b)
Yield: 0.27 g (59%); off-white solid; mp 78–80 °C; [a]D +160.3
(c 1.18, CHCl3).
IR (Nujol): 1580, 1509, 1334, 1269, 1238, 1174, 1126, 1104, 1035
cm–1.
25
1H NMR (300 MHz, CDCl3): d = 6.77 (d, J = 7.0 Hz, 2 H, ArH),
6.60 (d, J = 6.7 Hz, 2 H, ArH), 3.73 (s, 3 H, OMe), 3.66 (dd,
J = 10.9, 4.1 Hz, 1 H, H-1), 3.51 (dd, J = 10.7, 5.6 Hz, 1 H, H-1),
3.21–3.05 (m, 2 H, H-3), 2.99 (m, 1 H, H-2), 2.16 (br s, 3 H, 3 ×
NH).
13C NMR (75 MHz, CDCl3): d = 152.7, 142.8, 115.3, 114.8, 65.9,
56.2, 52.3, 49.1.
IR (CHCl3): 3369, 2929, 2832, 1655, 1514, 1465, 1357, 1302, 1236,
1117, 1037, 821 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.77 (d, J = 6.8 Hz, 4 H, ArH),
6.60 (d, J = 6.9 Hz, 4 H, ArH), 4.51–4.44 (m, 2 H, H-4), 4.39 (dd,
J = 9.6, 7.9 Hz, 2 H, H-5), 4.24 (dd, J = 7.7, 6.8 Hz, 2 H, H-5), 3.83
(br s, 2 H, 2 × NH), 3.75 (s, 6 H, 2 × OMe), 3.30 (dd, J = 12.0, 4.1
Hz, 2 H, H-1¢), 3.17 (dd, J = 12.0, 4.8 Hz, 2 H, H-1¢), 1.57 (s, 6 H,
2 × Me).
13C NMR (75 MHz, CDCl3): d = 170.9, 152.6, 142.9, 115.2, 114.8,
71.4, 65.9, 56.2, 48.7, 39.3, 24.6.
MS (EI): m/z = 452 [M]+, 452, 136.
MS (EI): m/z = 196 [M]+, 136 [M – CHNH2CH2OH]+, 122, 108, 60
[M – PhNHCH2]+.
HRMS (EI): m/z calcd for C10H16N2O2Na [M + Na]+: 219.1104;
found: 219.1109.
(R)-2-Amino-3-[3-(trifluoromethyl)phenylamino]propan-1-ol
HRMS (EI): m/z calcd for C25H32N4O4Na [M + Na]+: 475.2316;
found: 475.2287.
(2c)
Yield: 5.14 g (55%); white solid; mp 94–97 °C [a]D30 +12.3 (c 1.05,
MeOH).
2,2-Bis{2-[(4R)-4-(3-(trifluoromethyl)phenylamino)methyl-1,3-
oxazolinyl]}propane (16c)
IR (Nujol): 1612, 1575, 1530, 1484, 1447, 1353, 1319, 1283, 1266,
1172, 1105, 1069, 1055 cm–1.
Yield: 0.52 g (51%); clear oil; [a]D30 +113.1 (c 1.12, CHCl3).
IR (CHCl3): 3391, 2928, 1655, 1617, 1497, 1445, 1344, 1319, 1283,
1249, 1162, 1118, 1069, 991, 784, 758, 698 cm–1.
1H NMR (300 MHz, CD3OD): d = 7.21 (t, J = 8.0 Hz, 1 H, ArH),
6.86–6.75 (m, 3 H, ArH), 3.59 (dd, J = 11.0, 4.8 Hz, 1 H, H-1), 3.49
(dd, J = 10.9, 5.7 Hz, 1 H, H-1), 3.20 (dd, J = 9.1, 7.4 Hz, 1 H, H-
2), 3.08–2.92 (m, 2 H, H-3).
13C NMR (75 MHz, CD3OD): d = 151.1, 132.8 (q, J = 31.4 Hz,
CCF3), 131.1, 126.4 (q, J = 271.5 Hz, CF3), 117.1, 114.1, 110.0, 66,
53.4, 47.9.
1H NMR (300 MHz, CDCl3): d = 7.20 (t, J = 7.9 Hz, 2 H, ArH),
6.90 (d, J = 7.5 Hz, 2 H, ArH), 6.78 (s, 2 H, ArH), 6.70 (d, J = 8.0
Hz, 2 H, ArH), 4.59–4.48 (m, 4 H, H-4, 2 × NH), 4.40 (dd, J = 9.4,
8.4 Hz, 2 H, H-5), 4.21 (dd, J = 8.0, 6.4 Hz, 2 H, H-5), 3.37 (dt,
J = 12.3, 3.8 Hz, 2 H, H-1¢), 3.24 (ddd, J = 12.1, 7.0, 5.0 Hz, 2 H,
H-1¢), 1.56 (s, 6 H, 2 × Me).
13C NMR (75 MHz, CDCl3): d = 171.4, 148.9, 131.8 (q, J = 31.6
Hz, CCF3), 124.7 (q, J = 272.5 Hz, CF3), 116.2, 114.3, 114.2, 109.7,
109.6, 109.6, 71.2, 65.7, 47.2, 39.5, 24.4.
MS (EI): m/z = 234 [M]+, 174 [M – CHNH2CH2OH]+, 60 [M –
CH2NHC6H4CF3]+.
HRMS (EI): m/z calcd for C10H14N2OF3 [M + H]+: 235.1053; found:
235.1051.
MS (EI): m/z = 529 [M + H]+, 490, 446, 355, 286, 174, 139, 113.
Bis(oxazoline); General Procedure
HRMS (EI): m/z calcd for C25H27N4O2F6 [M + H]+: 529.2032;
found: 529.2024.
A solution of bis(amino) alcohol 2 (2.5 equiv), dimethylmalononi-
trile (1.0 equiv), Cd(OAc)2·2H2O (0.05 equiv) in chlorobenzene
(0.3 M) was heated at reflux overnight. Upon cooling to r.t., the dark
brown solution was poured into H2O (10 mL) and extracted with
CH2Cl2 (3 × 15 mL). The combined organics were washed with
brine (40 mL) and dried (MgSO4). After removing the solvent under
reduced pressure the residue was purified by column chromatogra-
phy (SiO2; MeOH–CH2Cl2, 1.5–2.0%).
Acknowledgment
Financial support from the University of Sussex is gratefully
acknowledged.
Synthesis 2005, No. 19, 3446–3450 © Thieme Stuttgart · New York

3450
J. A. Griffith, G. J. Rowlands
PAPER
(9) Kawakami, K.; Takahashi, H.; Ohki, H.; Kimura, K.;
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