Chiral furan-2-yl-substituted reagents based on (+)-α- methylbenzylamine

Article abstract of DOI:10.1134/S1070428012030189

The Schiff base obtained by condensation of furfural with (+)-α-methylbenzylamine was reduced with sodium tetrahydridoborate, and the resulting amine was alkylated with methyl iodide to obtain the corresponding chiral tertiary amine. Oxidation of the redu

Full text of DOI:10.1134/S1070428012030189

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 3, pp. 439–441. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © Z.R. Valiullina, S.S. Gataullin, B.Ya. Tsirel’son, R.F. Valeev, M.S. Miftakhov, 2012, published in Zhurnal Organicheskoi Khimii,
2012, Vol. 48, No. 3, pp. 439–441.
Chiral Furan-2-yl-Substituted Reagents
Based on (+)-α-Methylbenzylamine
Z. R. Valiullina, S. S. Gataullin, B. Ya. Tsirel’son, R. F. Valeev, and M. S. Miftakhov
Institute of Organic Chemistry, Ufa Research Center, Russian Academy of Sciences,
pr. Oktyabrya 71, Ufa, 450054 Bashkortostan, Russia
e-mail: bioreg@anrb.ru
Received July 25, 2011
Abstract—The Schiff base obtained by condensation of furfural with (+)-α-methylbenzylamine was reduced
with sodium tetrahydridoborate, and the resulting amine was alkylated with methyl iodide to obtain the
corresponding chiral tertiary amine. Oxidation of the reduction product with m-chloroperoxybenzoic acid gave
(1R)-N-(furan-2-ylmethylidene)-1-phenylethanamine N-oxide.
DOI: 10.1134/S1070428012030189
Continuously increasing needs of medicinal chem-
istry in enantiomerically pure compounds stimulate
development of new chiral reagents for asymmetric
synthesis. For this purpose, relatively inexpensive and
accessible (+)- and (–)-α-methylbenzylamines are
widely used as source of chirality [1, 2]. In the present
communication we report on the synthesis of homo-
chiral tertiary amine I and nitrone II from (+)-α-meth-
ylbenzylamine through secondary amine III [3].
chiral tertiary amines NR3 [15], etc. The use of nitrones
may be illustrated by two most important reactions,
1,3-dipolar cycloaddition to unsaturated compounds
and addition of nucleophiles [16, 17]. Examples of
using sterically hindered nitrones as spin trap for hy-
droxy radicals were given in [18].
By condensation of furfural with (+)-α-methylben-
zylamine with simultaneous removal of liberated water
we obtained Schiff base IV which was reduced (with-
out additional purification) with sodium tetrahydrido-
borate (Scheme 1). After chromatographic purification
on silica gel, the yield of amine III was more than
90%. An analytical sample of Schiff base IV can be
obtained by purification of the crude product by col-
umn chromatography on silica gel.
R
O–
N
Ph
Me
Ph
Me
N
O
O
I, III
II
I, R = Me; III, R = H.
Chiral secondary amines have found diverse ap-
plications in asymmetric synthesis. In particular, they
were used to develop methods for desymmetrization of
cyclic meso-anhydrides [4], imides [5], and epoxides
[6], asymmetric deprotonation of prochiral cyclic
ketones [7], catalytic conjugate addition [8], stereo-
selective aldol reactions [9], etc. [10]. Chiral tertiary
amines were also used: P,N-containing rhodium cata-
lysts for asymmetric hydrogenation of olefins were
described [11, 12]; condensations of organometallic
compounds with aldehydes, catalyzed by chiral tertiary
amines were reported [13]; Sharpless osmium com-
plexes based on quinine and cinchonidine catalyzed
asymmetric dihydroxylation of olefins [14]; Baylis–
Hillman reaction was performed in the presence of
Scheme 1.
H2N
Ph
+
CHO
O
Me
NaBH4
MeOH, 0°C
Ph
Me
PhMe, reflux
N
III
O
IV
Tertiary amine I was synthesized by metalation of
compound III with butyllithium and subsequent
alkylation with methyl iodide. The oxidation of III
with m-chloroperoxybenzoic acid smoothly afforded
nitrone II. The latter can also be prepared directly from
Schiff base IV by oxidation with the same reagent, but
439

VALIULLINA et al.
base IV was obtained by purification of the product by
440
Scheme 2.
Me
column chromatography on silica gel deactivated with
triethylamine; petroleum ether–ethyl acetate (100:3)
was used as eluent. Oily substance, Rf 0.40 (petroleum
ether–ethyl acetate, 8:1, double elution), [α]D20 = –73°
(c = 1.0, CHCl3). IR spectrum, ν, cm–1: 1691, 1678
(1) BuLi, THF
(2) MeI
Ph
Me
N
O
I
III
1
O–
N
(C=C); 1645 (C=N), 1016 (C–O–C). H NMR spec-
m-ClC6H4CO3H
CH2Cl2
Ph
Me
trum, δ, ppm: 1.63 d (3H, Me, J = 6.5 Hz), 4.50 q (1H,
CHMe, J = 6.5 Hz), 6.45 m (1H, 4-H), 6.74 m (1H,
3-H), 7.20–7.46 m (5H, Ph), 7.52 d (1H, 5-H, J =
1.7 Hz), 8.14 s (1H, CH=N). 13C NMR spectrum, δC,
ppm: 24.57 (Me), 69.95 (CHMe), 111.62 (C3), 114.42
(C4), 126.78 (Co), 127.02 (Cp), 128.52 (Cm), 144.63
(Ci), 144.78 (CH=N), 148.39 (C5), 151.59 (C2). Mass
spectrum, m/z (Irel, %): 199 (46) [M]+, 184 (19) [M –
Me]+, 105 (100) [M – N=CHC4H3O]+. Found, %:
C 78.20; H 6.71; N 7.11. C13H13NO. Calculated, %:
C 78.36; H 6.58; N 7.03.
O
II
Ph
Me
N
O
O
V
in this case the reaction was accompanied by formation
of a considerable amount of nonpolar oxaziridine V as
a mixture of diastereoisomer at a ratio of 4:1.
(1R)-N-(Furan-2-ylmethyl)-1-phenylethanamine
(III). The crude product containing Schiff base IV (see
above) was dissolved in 35 ml of anhydrous methanol,
2.15 g (0.048 mol) of 85% sodium tetrahydridoborate
was added at 0°C under stirring in an argon atmos-
phere, the mixture was stirred for 2 h (TLC), 8 ml of
acetone was added dropwise at 0°C, and 5 ml of
a saturated aqueous solution of ammonium chloride
was then added. Methanol was distilled off, the residue
was extracted with ethyl acetate, the extract was
washed with saturated solutions of ammonium chloride
and sodium chloride, dried over MgSO4, and concen-
trated under reduced pressure, and the residue was
purified by column chromatography on silica gel using
petroleum ether–ethyl acetate (9:1) as eluent. Yield
7.68 g (93% calculated on the initial furfural), oily
substance, Rf 0.33 (petroleum ether–ethyl acetate, 9:1,
double elution), [α]D20 = +78.4° (c = 1.0, CHCl3);
(neither [α]D20 nor spectral parameters of compound III
were given in [3]). IR spectrum, ν, cm–1: 3320 (N–H);
The furyl substituent in compounds I–III is ex-
pected to act as an additional coordinating fragment in
metal-catalyzed reactions and as a latent functional
group.
EXPERIMENTAL
The IR spectra were recorded on a Shimadzu IR
Prestige-21 spectrometer from films or dispersions in
mineral oil. The H and 13C NMR spectra were meas-
1
ured on a Bruker AM-300 instrument at 300.13 and
75.47 MHz, respectively, using CDCl3 as solvent and
reference (CHCl3, δ 7.27 ppm; CDCl3, δC 77.00 ppm).
The mass spectra (electron impact, 70 eV) were ob-
tained on a Thermo Finnigan MAT 95XP mass spec-
trometer. The progress of reactions was monitored by
TLC on Sorbfil plates; spots were detected by treat-
ment with a 10% solution of 4-methoxybenzaldehyde
in ethanol containing sulfuric acid or with an alkaline
solution of potassium permanganate. The optical
rotations were determined on a Perkin Elmer 241 MC
polarimeter. (+)-α-Methylbenzylamine was commer-
cial product (Fluka), [α]D25 = +38.5°.
1
1369, 1211 (C–N). H NMR spectrum, δ, ppm: 1.38 d
(3H, Me, J = 6.6 Hz), 1.70 br.s (1H, NH), 3.55 d and
3.65 d (1H each, NCH2, J = 14.4 Hz), 3.80 q (1H,
CHMe, J = 6.6 Hz), 6.11 d.d (1H, 3-H, J = 0.5,
3.0 Hz), 6.30 d.d (1H, 4-H, J = 1.6, 3.0 Hz), 7.25–
7.40 m (6H, 5-H, Ph). 13C NMR spectrum, δC, ppm:
24.39 (Me), 44.06 (CH2), 57.13 (CHMe), 106.87 (C3),
110.16 (C4), 126.85 (Co), 127.12 (Cp), 128.59 (Cm),
141.80 (C5), 145.19 (Ci), 154.15 (C2). Mass spectrum,
m/z (Irel, %): 186 (100) [M – Me]+, 105 (14) [M –
NHCH2C4H3O]+, 81 (58) [M – NHCH(Me)Ph]+.
Found, %: C 77.50; H 7.54; N 7.01. C13H13NO. Cal-
culated, %: C 77.58; H 7.51; N 6.96.
(1R)-N-(Furan-2-ylmethylidene)-1-phenylethan-
amine (IV). A solution of 3.94 g (0.041 mmol) of
furfural and 5.00 g (0.041 mmol) of (+)-α-methylben-
zylamine in 10 ml of anhydrous toluene was heated
under reflux in a flask equipped with a Dean–Stark
trap until water no longer separated. The mixture was
concentrated under reduced pressure and was subjected
to subsequent reduction. An analytical sample of Schiff
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 3 2012

CHIRAL FURAN-2-YL-SUBSTITUTED REAGENTS
441
(1R)-N-Methyl-N-(furan-2-ylmethyl)-1-phenyl-
ethanamine (I). A solution of 1.4 g (6.97 mmol) of
amine III in 20 ml of anhydrous THF was cooled to
–78°C, 7.0 ml (10.45 mmol) of a 1.5 N solution of
butyllithium in hexane was added dropwise under
stirring, the mixture was allowed to warm up to –20°C,
stirred for 30 min, and cooled again to –78°C, and
a solution of 0.87 ml (13.93 mmol) of methyl iodide in
5 ml of anhydrous THF was added dropwise. The mix-
ture was allowed to slowly warm up to room tempera-
ture, stirred for 1 h until the initial compound disap-
peared, and treated with a saturated solution of ammo-
nium chloride, the organic phase was separated, and
the aqueous phase was extracted with ethyl acetate
(2 ×10 ml). The extracts were combined with the
organic phase, dried over MgSO4, and concentrated
under reduced pressure, and the residue was purified
by column chromatography on silica gel using petro-
leum ether–ethyl acetate (10:1) as eluent. Yield 1.2 g
(80%), light yellow liquid, [α]D20 = +69.6° (c = 4.57,
CHCl3). IR spectrum, ν, cm–1: 1310 (C–N), 1013
(C–O–C). 1H NMR spectrum, δ, ppm: 1.43 d (3H, Me,
J = 6.3 Hz), 2.23 s (3H, NMe), 3.44 d (1H, NCH2, J =
14.4 Hz), 3.58 q (1H, CHMe, J = 6.3 Hz), 3.67 d (1H,
NCH2, J = 14.4 Hz), 6.16–6.17 m (1H, 3-H), 6.31–
6.33 m (1H, 4-H), 7.26–7.39 m (6H, 5-H, Ph). 13C NMR
spectrum, δC, ppm: 19.63 (Me), 38.81 (NMe), 50.92
(CHMe), 62.67 (CH2), 108.24 (C3), 109.93 (C4),
126.86 (Co), 127.55(Cp), 128.20 (Cm), 141.76 (C5),
143.81 (Ci), 152.79 (C2).
3.3 Hz), 7.35–7.50 m (6H, 4-H, Ph), 7.61 s (1H,
CH=N), 7.77 d (1H, 5-H, J = 3.5 Hz). C NMR spec-
13
trum, δC, ppm: 18.83 (Me), 73.41 (CHMe), 112.09
(C3), 114.96 (C4), 123.83 (CH=N), 127.12 (Co, Cp),
128.62 (Cm), 138.06 (Ci), 143.34 (C5), 146.74 (C2).
Mass spectrum, m/z (Irel, %): 215 (9.5) [M]+, 105 (100)
[M – N(O)=CHC4H3O]+. Found, %: C 72.53; H 6.18;
N 6.60. C13H13NO2. Calculated, %: C 72.54; H 6.04;
N 6.51.
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