An unprecedented ring transformation of a 4-(aminomethyl)oxazoline derivative to a 4-(hydroxymethyl)imidazoline

Article abstract of DOI:10.1055/s-0033-1340044

An optically active 4-(azidomethyl)-2-(2-pyridyl)oxazoline was prepared starting from l-serine and picolinic acid. Reduction of the azide moiety gave the corresponding 4-(aminomethyl)-2-(2-pyridyl)oxazoline, which is not a stable compound but readily unde

Full text of DOI:10.1055/s-0033-1340044

PAPER
▌81
paper
An Unprecedented Ring Transformation of a 4-(Aminomethyl)oxazoline
Derivative to a 4-(Hydroxymethyl)imidazoline
Ring Transformation of a 4-(Aminomethyl)oxazoline
Marvin Schulz, Jens Christoffers*
Institut für Chemie, Carl von Ossietzky Universität Oldenburg, 26111 Oldenburg, Germany
Fax +49(441)7983873; E-mail: jens.christoffers@uni-oldenburg.de
Received: 27.08.2013; Accepted after revision: 30.09.2013
The starting point of our investigation was the hydroxy-
methyl compound 7, which was obtained by the five-step
sequence outlined in Scheme 2. Picolinic acid (3) was first
coupled with methyl L-serinate10 to give amide 4 (71%).11
Abstract: An optically active 4-(azidomethyl)-2-(2-pyridyl)oxazo-
line was prepared starting from L-serine and picolinic acid. Reduc-
tion of the azide moiety gave the corresponding 4-(aminomethyl)-
2-(2-pyridyl)oxazoline, which is not a stable compound but readily
undergoes ring-transformation rearrangement to furnish a 4-(hy- The primary alcohol was then TBS protected (92% yield
of compound 5)12 and the ester moiety reduced to again
give a primary alcohol 8 (79%), which was activated with
droxymethyl)-2-(2-pyridyl)imidazoline. After Boc protection of the
amidine function, the material could be further converted into the 4-
(aminomethyl)-2-(2-pyridyl)imidazoline via the respective azido-
tosyl chloride and cyclized according to a literature proto-
methyl compound.
col.13 Intermediate product 6 (77%) was finally deprotect-
ed with tetrabutylammonium fluoride (93% yield of
product 7).
Key words: heterocycles, oxazolines, imidazolines, pyridines, chi-
ral ligands
OR
Since the first reports by Brunner and co-workers,1 opti-
cally active 2-pyridyloxazolines have become a privi-
HN
(a)
CO2H
CO2Me
leged class of chiral ligands in asymmetric catalysis.2,3 In
continuation of our earlier work on C1-symmetric, triden-
tate pyridyloxazolines,4 we were planning to prepare com-
pound 1 with an aminomethyl group, the latter being
perfectly suited for further N-functionalization, for exam-
ple by amidation reactions. In the event, we were unable
to isolate compound 1, nor its derivatives, as it always un-
derwent ring transformation to furnish the hydroxymeth-
yl-functionalized pyridylimidazoline 2 (Scheme 1). Such
a ring transformation has been reported once before for
the formation of a cyclic urea from a urethane.5 It has been
at least suspected for [(N-arylamino)methyl]oxazolines,6
but not observed by others, although some researchers
claim to have isolated an (aminomethyl)oxazoline as an
intermediate product.7 In one other case, an in situ formed
(aminomethyl)oxazoline was protected with CbzCl in the
reaction mixture.8 Since optically active imidazolines are
an increasingly important, novel class of chiral ligands,9
investigations on further conversion of the product 2
seemed promising to us. Therefore, we now report on the
preparation of compound 1 and its transformation to imid-
azoline 2, as well as some further chemistry starting with
the latter compound.
N
N
O
3
4 R = H, 71%
(b)
5 R = TBS, 92%
(c)
OTBS
OH
HN
O
N
(d)
OR
N
N
O
6 R = TBS, 77%
7 R = H, 93%
8 79%
(e)
Scheme 2 Preparation of hydroxymethyl compound 7. Reagents and
conditions: (a) NMM (2.3 equiv), ClCO2Et (1.1 equiv), (S)-
MeO2CCH(CH2OH)NH2·HCl (1.1 equiv), THF, 0 °C to r.t., 2 h; (b)
TBSCl (1.3 equiv), imidazole (3 equiv), CH2Cl2, r.t., 1 h; (c) LiBH4
(1.3 equiv), THF, 0 °C, 3 h; (d) TsCl (1.2 equiv), DMAP (0.1 equiv),
DCE, reflux, 16 h; (e) TBAF·3H2O (1.2 equiv), THF, r.t., 1 h; TBS =
t-BuMe2Si, Ts = 4-MeC6H4SO2.
Organoazides are excellent precursors for primary
amines; therefore, we activated the primary alcohol func-
tion of compound 7 by sulfonyl ester formation (95% of
product 9) and converted it with sodium azide in ethanol
following common protocols (Scheme 3).14 Product 10,
after chromatography, was obtained in almost quantitative
yield. Azide 10 was subjected to catalytic hydrogenation
to again give a single compound (95% yield) with correct
mass (ESI) and 1H and 13C NMR spectra that seemed to be
in agreement with structure 1; however, all attempts at
further derivatization of what we assumed to be an amino
function, in particular amide formation, failed. We real-
ized that the ring-transformation reaction of intermediate
product 1 with formation of imidazoline 2 would be an ex-
planation for our failure to produce amides of purported
H
N
N
NH2
OH
O
N
N
N
1
2
Scheme 1 Facile ring transformation of 4-(aminomethyl)oxazoline
1 to 4-(hydroxymethyl)imidazoline 2
SYNTHESIS 2014, 46, 0081–0086
Advanced online publication: 04.11.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1340044; Art ID: SS-2013-T0591-OP
© Georg Thieme Verlag Stuttgart · New York

82
M. Schulz, J. Christoffers
PAPER
1
amine 1. Imidazoline 2 would give similar H and 13C bamate N-1 showed three strong cross peaks, to 4-H and
NMR spectra, leading us astray. This rearrangement ap- both 5-H protons, whereas the imine N-3 showed two
pears obvious, since the amino group as a good nucleo- strong cross peaks, to both 4-CH2OH protons, and one
phile is at the right distance to form a bicyclo[2.2.1] weak cross peak, to one 5-H proton.
intermediate structure when adding to the electrophilic
imidoester group.
Boc
H
N
N
(a)
O
O
(b)
OR
OH
N
N
N
N
OR
N3
11 R = H, 67%
2
N
N
N
N
(b)
7 R = H
10 99%
12 R = Ts, 40%
(a)
9 R = Ts, 95%
(c)
(c)
H
N
O
Boc
Boc
N
N
(d)
OH
NH2
N
N
N
N
2 95%
1
N3
NH2
N
N
N
N
13 73%
14 67%
Scheme 3 Preparation and ring transformation of 4-(aminometh-
yl)oxazoline 1. Reagents and conditions: (a) TsCl (1.5 equiv), KOH,
H2O, CH2Cl2, reflux, 3 h; (b) NaN3 (5 equiv), EtOH, reflux, 16 h; (c)
H2 (1 atm), Pd/C (cat.), MeOH, 23 °C, 16 h.
Scheme 4 Preparation and reduction of azide 13. Reagents and con-
ditions: (a) Boc2O (2.5 equiv), K2CO3 (2 equiv), H2O, THF, reflux, 24
h; (b) TsCl (6.3 equiv), KOH, H2O, CH2Cl2, reflux, 3 h; (c) NaN3 (5
equiv), EtOH, reflux, 16 h; (d) H2 (1 atm), Pd/C (cat.), MeOH, 23 °C,
16 h.
Definite proof of the structure of compound 2 came from
its subsequent chemistry, which was initially difficult as
the very basic amidine function caused several problems The alcohol function of 11 could then be activated by to-
with chemoselectivity. These problems could, however, sylate formation (40% yield of product 12) and subse-
be solved by reducing the electron density of 2 by install- quently be displaced with azide to furnish compound 13
ing a carbamate function (product 11, 67% yield of crude (73% yield). Finally, the aminomethyl compound 14 was
material; Scheme 4). Interestingly, we obtained a single obtained by hydrogenation of azide 13 (67% yield), and
compound, although one would expect a regioselectivity actually represents the N-Boc-imidazoline congener of
problem due to the presence of two nucleophilic nitrogen our initial target compound 1. This material 14 will now
atoms at the amidine function. The depicted regiochemis- be the cornerstone in future efforts for the synthesis of
try was proven by 2D-NMR spectroscopy, after the as- new libraries of chiral polydentate ligands.
signment of all resonances. Firstly, C-4 and 4-H were
In summary, during our studies towards new, optically ac-
tive tridentate ligands, we considered aminomethyl-sub-
identified by DEPT135 and HMQC experiments [δ(13C) =
66.8, δ(1H) = 4.28 ppm]. Furthermore, the pyridine signals
stituted pyridyloxazoline 1 as a core structure which
were identified by H,H-COSY and HMQC experiments,
would be ready for further derivatization at the primary
amino function. However, attempts to prepare target com-
as follows [δ(1H), δ(13C), in ppm]: 7.5 (3′-H), 123.4 (C-
3′); 7.7 (4′-H), 136.3 (C-4′); 7.29 (5′-H), 124.3 (C-5′);
pound 1 by reduction of the respective azidomethyl pre-
8.58 (6′-H), 148.8 (C-6′). The quaternary pyridine C-2′
cursor 10 directly led to the rearranged product 2 with a
was then identified at 151.4 ppm (HMBC cross peaks with
hydroxymethyl-substituted imidazoline ring. This very
basic amidine moiety hindered subsequent chemistry and
was therefore protected with a tert-butoxycarbonyl group.
It was then possible to access the (aminomethyl)(pyri-
6′-H and 4′-H). Of the two remaining sp2-carbon reso-
nances, the amidine C-2 was assigned at δ = 159.4 ppm by
the HMBC cross peak with 3′-H. Therefore, the carbamate
C=O must be the remaining sp2 signal at δ = 150.4 ppm.
dyl)imidazoline 14 which is now ready for further diver-
The two methylene protons 5-H were then identified at
sifying derivatization at the primary amino function.
δ = 3.84 and 3.99 ppm by the HMBC cross peak with the
amidine C-2; the respective C-5 was identified at δ = 49.3
Preparative column chromatography was carried out using Merck
silica gel (35–70 μm, type 60 A) with hexane, EtOAc and MeOH as
eluents. The column dimensions are given as follows: diameter ×
ppm (HMQC experiment). The remaining 4-CH2OH was
identified at δ(1H) = 3.64 and 3.74 ppm, and δ(13C) = 64.3
ppm (HMQC experiment). With this assignment of all
height. TLC was performed on Merck aluminum plates coated with
1
silica gel F254. H, 13C and 15N NMR spectra were recorded on a
Bruker Avance DRX 500 instrument. Multiplicities of carbon sig-
nals were determined with DEPT experiments. MS and HRMS
spectra were obtained with a Waters Q-Tof Premier (ESI) spectrom-
eter. IR spectra were recorded on a Bruker Tensor 27 spectrometer
equipped with a Golden Gate diamond ATR unit. Elemental analy-
ses were determined with a Euro EA-CHNS instrument from
HEKAtech. Optical rotations were measured with a Polartronic M
polarimeter from Schmidt and Haensch. Methyl L-serinate hydro-
proton and carbon resonances in hand, the structure of
compound 11 was finally proven by 15N,1H-HMBC spec-
troscopy; three 15N signals were observed, and were as-
signed according to the literature data for a similar 1-
acetyl-2-aryl-4,5-dihydroimidazole:15 δ(15N) = –74.1 (N-
1′), –122.8 (N-3), –244.5 (N-1) ppm, with MeNO2 (δ = 0)
as external standard. Naturally, within the pyridine ring,
N-1′ showed cross peaks to 3′-H, 5′-H and 6′-H. The car-
Synthesis 2014, 46, 81–86
© Georg Thieme Verlag Stuttgart · New York

PAPER
Ring Transformation of a 4-(Aminomethyl)oxazoline
83
chloride was prepared according to a literature procedure.10 All oth-
er starting materials were commercially available.
removed under reduced pressure. The residue was purified by col-
umn chromatography (silica gel, 7 cm × 12 cm; EtOAc–hexane, 1:1,
Rf = 0.20) to yield compound 8 (6.88 g, 22.2 mmol, 79%) as a col-
orless liquid.
Methyl (S)-N-(2-Pyridylcarbonyl)serinate (4)
N-Methylmorpholine (10.3 mL, 9.46 g, 93.5 mmol) and ethyl chlo-
roformate (4.20 mL, 4.85 g, 44.7 mmol) were added to an ice-
cooled suspension of picolinic acid (3) (5.00 g, 40.6 mmol) in anhy-
drous THF (50 mL) and the mixture was stirred for 0.5 h at this tem-
perature. Methyl L-serinate hydrochloride (7.00 g, 44.7 mmol) was
added and, after further stirring for 2 h at r.t., the solvent was re-
moved under reduced pressure. The residue was partitioned be-
tween EtOAc (50 mL) and H2O (50 mL), and the aqueous layer was
extracted with EtOAc (2 × 50 mL). The combined organic layers
were dried (MgSO4) and filtered, and the solvent was removed un-
der reduced pressure. The residue was purified by column chroma-
tography (silica gel, 7 cm × 11 cm; EtOAc–hexane, 2:1, Rf = 0.25)
to yield compound 4 (6.46 g, 28.8 mmol, 71%) as a colorless liquid.
All spectroscopic data were in accordance with the literature.11
[α]D20 +3.33 (c 1.00, CH2Cl2).
IR (ATR): 3384 (m), 2955 (m), 2931 (m), 2885 (w), 2859 (m), 1666
(s), 1593 (w), 1572 (w), 1521 (s), 1466 (m), 1436 (m), 1391 (w),
1363 (w), 1293 (w), 1255 (m), 1091 (s), 1046 (m), 1022 (m), 1000
(m), 940 (w), 835 (s), 779 (s) cm–1.
1H NMR (500 MHz, CDCl3): δ = 0.08 (s, 3 H), 0.09 (s, 3 H), 0.92
(s, 9 H), 3.01 (dd, J = 7.8, 4.0 Hz, 1 H), 3.80–3.85 (m, 1 H), 3.86–
3.98 (m, 3 H), 4.13–4.20 (m, 1 H), 7.42 (ddd, J = 7.7, 4.7, 1.2 Hz, 1
H), 7.85 (td, J = 7.7, 1.6 Hz, 1 H), 8.19 (dt, J = 7.8, 1.0 Hz, 1 H),
8.56 (ddd, J = 4.8, 1.6, 0.8 Hz, 1 H), 8.63–8.67 (m, 1 H).
13C{1H} NMR (125 MHz, CDCl3): δ = –5.6 (CH3), –5.4 (CH3), 18.3
(C), 26.0 (3 CH3), 52.5 (CH), 63.8 (CH2), 64.2 (CH2), 122.3 (CH),
126.3 (CH), 137.4 (CH), 148.4 (CH), 150.0 (C), 164.9 (C).
[α]D20 +38.9 (c 1.03, CH2Cl2) [Lit.11 [α]D21 +39.4 (c 2.5, CHCl3)].
HRMS (ESI, positive mode): m/z [M
C15H26N2NaO3Si: 333.1610; found: 333.1612.
+
Na+] calcd for
1H NMR (500 MHz, CDCl3): δ = 2.87 (t, J = 5.7 Hz, 1 H, OH), 3.82
(s, 3 H), 4.03–4.14 (m, 2 H), 4.87 (dt, J = 7.7, 3.9 Hz, 1 H), 7.44
(ddd, J = 7.6, 4.8, 1.0 Hz, 1 H), 7.84 (td, J = 7.7, 1.7 Hz, 1 H), 8.16
(dt, J = 7.9, 1.0 Hz, 1 H), 8.58 (ddd, J = 4.8, 1.5, 0.9 Hz, 1 H), 8.80–
8.85 (m, 1 H, NH).
13C{1H} NMR (125 MHz, CDCl3): δ = 52.8 (CH), 54.9 (CH3), 63.5
(CH2), 122.4 (CH), 126.5 (CH), 137.3 (CH), 148.3 (CH), 149.1 (C),
164.7 (C), 170.7 (C).
Anal. Calcd for C15H26N2O3Si (310.47): C, 58.03; H, 8.44; N, 9.02.
Found: C, 58.01; H, 8.44; N, 9.02.
(R)-4-(tert-Butyldimethylsilyloxymethyl)-2-(2-pyridyl)-4,5-di-
hydrooxazole (6)
TsCl (1.47 g, 7.73 mmol), DMAP (78 mg, 0.64 mmol) and Et3N
(4.48 mL, 3.26 g, 32.2 mmol) were added to a solution of compound
8 (2.00 g, 6.44 mmol) in DCE (40 mL) and the resulting mixture
was heated to reflux for 16 h. The organic layer was washed with
H2O (3 × 30 mL), dried (MgSO4) and filtered, and the solvent was
removed under reduced pressure. The residue was purified by col-
umn chromatography (silica gel, 5 cm × 12 cm; EtOAc–hexane, 1:1,
Rf = 0.20) to yield compound 6 (1.45 g, 4.96 mmol, 77%) as a col-
orless liquid.
Methyl (S)-O-(tert-Butyldimethylsilyl)-N-(2-pyridylcarbon-
yl)serinate (5)
TBSCl (4.81 g, 31.9 mmol) and imidazole (5.00 g, 73.5 mmol) were
added to a solution of compound 4 (5.49 g, 24.5 mmol) in CH2Cl2
(70 mL), and the mixture was stirred for 1 h at r.t. and then filtered.
The solvent was removed under reduced pressure and the residue
was purified by column chromatography (silica gel, 7 cm × 11 cm;
EtOAc–hexane, 1:2, Rf = 0.40) to yield compound 5 (7.66 g, 22.6
mmol, 92%) as a colorless liquid.
[α]D20 –37.5 (c 0.99, CH2Cl2).
IR (ATR): 2955 (m), 2930 (m), 2899 (w), 2858 (m), 1643 (m), 1585
(w), 1572 (w), 1519 (w), 1473 (m), 1442 (m), 1363 (m), 1253 (m),
1109 (m), 1045 (m), 1009 (m), 967 (m), 940 (w), 897 (w), 835 (s),
803 (m), 777 (s), 746 (m) cm–1.
1H NMR (500 MHz, CDCl3): δ = 0.04 (s, 3 H), 0.07 (s, 3 H), 0.86
(s, 9 H), 3.65–3.70 (m, 1 H), 3.94 (dd, J = 10.2, 3.4 Hz, 1 H), 4.42–
4.50 (m, 2 H), 4.51–4.57 (m, 1 H), 7.38 (ddd, J = 7.6, 4.8, 1.1 Hz, 1
H), 7.77 (td, J = 7.8, 1.6 Hz, 1 H), 8.03 (dt, J = 7.9, 1.0 Hz, 1 H),
8.70 (ddd, J = 4.8, 1.7, 0.9 Hz, 1 H).
[α]D20 +35.3 (c 1.13, CH2Cl2).
IR (ATR): 3396 (w), 2953 (w), 2930 (w), 2885 (w), 2857 (w), 1749
(m), 1680 (m), 1592 (w), 1571 (w), 1512 (s), 1465 (m), 1435 (m),
1380 (w), 1352 (m), 1292 (w), 1253 (m), 1207 (m), 1168 (m), 1107
(s), 1043 (m), 998 (m), 965 (w), 939 (w) cm–1.
1H NMR (500 MHz, CDCl3): δ = 0.009 (s, 3 H), 0.011 (s, 3 H), 0.89
(s, 9 H), 3.75 (s, 3 H), 3.95 (dd, J = 10.1, 3.5 Hz, 1 H), 4.19 (dd, J =
10.1, 3.0 Hz, 1 H), 4.86 (dt, J = 8.6, 3.2 Hz, 1 H), 7.43 (ddd, J = 7.6,
4.7, 1.2 Hz, 1 H), 7.84 (td, J = 7.7, 1.7 Hz, 1 H), 8.18 (dt, J = 7.8,
1.1 Hz, 1 H), 8.60 (ddd, J = 4.8, 1.6, 0.8 Hz, 1 H), 8.74–8.78 (m, 1
H).
13C{1H} NMR (125 MHz, CDCl3): δ = –5.2 (2 CH3), 18.4 (C), 26.0
(3 CH3), 65.2 (CH2), 68.7 (CH), 71.2 (CH2), 124.0 (CH), 125.7
(CH), 136.7 (CH), 147.0 (C), 149.9 (CH), 164.1 (C).
13C{1H} NMR (125 MHz, CDCl3): δ = –5.6 (CH3), –5.5 (CH3), 18.3
(C), 25.8 (3 CH3), 52.5 (CH), 54.6 (CH3), 63.8 (CH2), 122.4 (CH),
126.4 (CH), 137.3 (CH), 148.5 (CH), 149.7 (C), 164.3 (C), 170.9
(C).
HRMS (ESI, positive mode): m/z [M
C15H24N2NaO2Si: 315.1505; found: 315.1500.
+
Na+] calcd for
Anal. Calcd for C15H24N2O2Si (292.45): C, 61.60; H, 8.27; N, 9.58.
Found: C, 61.59; H, 8.29; N, 9.52.
HRMS (ESI, positive mode): m/z [M
+
Na+] calcd for
(S)-4-(Hydroxymethyl)-2-(2-pyridyl)-4,5-dihydrooxazole (7)
TBAF·3H2O (1.94 g, 6.16 mmol) was added to a solution of com-
pound 6 (1.50 g, 5.13 mmol) in THF (50 mL) and the resulting mix-
ture was stirred for 1 h at r.t. The solvent was removed under
reduced pressure and the residue was purified by column chroma-
tography (silica gel, 5 cm × 10 cm; EtOAc–MeOH, 5:1, Rf = 0.24)
to yield compound 7 (0.850 g, 4.77 mmol, 93%) as a colorless oil.
C16H26N2NaO4Si: 361.1560; found: 361.1552.
Anal. Calcd for C16H26N2O4Si (338.48): C, 56.78; H, 7.74; N, 8.28.
Found: C, 56.77; H, 7.82; N, 8.40.
N-[(R)-2-(tert-Butyldimethylsilyloxy)-1-(hydroxymethyl)eth-
yl]picolinamide (8)
Compound 5 (9.48 g, 28.0 mmol) was added dropwise to an ice-
cooled solution of LiBH4 (18.3 mL of a 2 M solution in THF, 36.6
mmol; diluted with 18.3 mL anhydrous THF) and the mixture was
stirred for 3 h at this temperature. Subsequently, H2O (10 mL) and
10% HCl (ca. 20 mL) were added with caution. After gas evolution
had stopped, sat. aq NaHCO3 solution (ca. 40 mL) was added and
the mixture was extracted with EtOAc (4 × 40 mL). The combined
organic layers were dried (MgSO4) and filtered, and the solvent was
[α]D20 –61.6 (c 0.69, MeOH).
IR (ATR): 3288 (m), 2982 (w), 2927 (w), 2874 (w), 1664 (m), 1582
(m), 1483 (m), 1432 (m), 1398 (w), 1381 (m), 1360 (s), 1343 (m),
1301 (m), 1285 (m), 1270 (m), 1247 (m), 1222 (m), 1199 (w), 1155
(w), 1125 (s), 1098 (m), 1086 (m), 1070 (s), 1042 (m), 995 (m), 983
(m), 952 (s), 933 (m), 908 (w), 890 (m) cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 81–86

84
M. Schulz, J. Christoffers
PAPER
1H NMR (500 MHz, CDCl3): δ = 3.18 (s, 1 H), 3.70 (dd, J = 11.6,
4.0 Hz, 1 H), 4.01 (dd, J = 11.6, 3.4 Hz, 1 H), 4.42–4.46 (m, 1 H),
4.47–4.53 (m, 1 H), 4.57 (dd, J = 9.5, 7.2 Hz, 1 H), 7.35 (ddd, J =
7.6, 4.8, 0.9 Hz, 1 H), 7.73 (td, J = 7.7, 1.7 Hz, 1 H), 7.93 (dt, J =
7.9, 1.2 Hz, 1 H), 8.64 (ddd, J = 4.8, 1.6, 0.9 Hz, 1 H).
HRMS (ESI, positive mode): m/z [M + Na+] calcd for C9H9N5NaO:
226.0705; found: 226.0699.
Anal. Calcd for C9H9N5O (203.21): C, 53.20; H, 4.46; N, 34.37.
Found: C, 53.16; H, 4.47; N, 34.29.
13C{1H} NMR (125 MHz, CDCl3): δ = 64.0 (CH2), 68.6 (CH), 70.0
(CH2), 124.0 (CH), 125.9 (CH), 136.8 (CH), 146.2 (C), 149.9 (CH),
164.5 (C).
(S)-4-(Hydroxymethyl)-2-(2-pyridyl)-4,5-dihydro-1H-imidaz-
ole (2)
A suspension of compound 10 (2.21 g, 10.9 mmol) and Pd/C (221
mg, 10% w/w Pd) in MeOH (50 mL) was degassed (three cycles of
freeze, pump and thaw) and then stirred under an atmosphere of H2
(1 atm) for 16 h at 23 °C. The mixture was filtered, then the solvent
was removed under reduced pressure to yield compound 2 (1.82 g,
10.3 mmol, 95%) as a yellow oil.
HRMS (ESI, positive mode): m/z [M
+
Na+] calcd for
C9H10N2NaO2: 201.0640; found: 201.0635.
(R)-4-[(4-Methylphenylsulfonyloxy)methyl]-2-(2-pyridyl)-4,5-
dihydrooxazole (9)
TsCl (1.07 g, 5.60 mmol) was added to a solution of compound 7
(0.665 g, 3.73 mmol) in 15% aq KOH solution (25 mL) and CH2Cl2
(25 mL), and the resulting mixture was heated to reflux for 3 h. The
layers were separated and the aqueous layer was extracted with
CH2Cl2 (50 mL). The combined organic layers were dried (MgSO4)
and filtered, and the solvent was removed under reduced pressure.
The residue was purified by column chromatography (silica gel, 5
cm × 8 cm; EtOAc–MeOH, 5:1, Rf = 0.40) to yield compound 9
(1.18 g, 3.56 mmol, 95%) as a colorless solid; mp 113 °C.
[α]D20 +55.3 (c 1.11, MeOH).
IR (ATR): 3279 (br), 2927 (m), 2862 (m), 2453 (w), 1659 (w), 1601
(m), 1566 (m), 1487 (m), 1456 (m), 1421 (m), 1331 (m), 1271 (m),
1189 (m), 1096 (m), 1045 (m), 979 (m), 801 (m) cm–1.
1H NMR (500 MHz, CD3OD): δ = 3.61 (dd, J = 11.0, 5.6 Hz, 1 H),
3.65 (dd, J = 11.1, 5.5 Hz, 1 H), 3.70 (dd, J = 12.3, 7.5 Hz, 1 H),
3.92 (dd, J = 12.2, 10.9 Hz, 1 H), 4.19 (ddt, J = 10.7, 7.5, 5.6 Hz, 1
H), 7.50 (ddd, J = 7.5, 4.9, 1.0 Hz, 1 H), 7.90 (td, J = 7.8, 1.7 Hz, 1
H), 8.02 (dt, J = 7.9, 1.0 Hz, 1 H), 8.63 (ddd, J = 4.9, 1.5, 1.1 Hz, 1
H).
[α]D20 –82.9 (c 1.15, CH2Cl2).
IR (ATR): 3055 (w), 2968 (w), 2902 (w), 2324 (w), 1732 (w), 1645
(m), 1599 (m), 1568 (m), 1494 (w), 1471 (m), 1442 (m), 1348 (m),
1306 (m), 1292 (m), 1280 (m), 1246 (m), 1213 (m), 1175 (s), 1121
(m), 1098 (m), 1080 (m), 1039 (m), 1012 (m), 994 (m), 966 (m), 948
(s), 932 (m), 898 (m), 866 (m) cm–1.
1H NMR (500 MHz, CDCl3): δ = 2.41 (s, 3 H), 4.05 (dd, J = 10.0,
6.6 Hz, 1 H), 4.29 (dd, J = 10.0, 3.7 Hz, 1 H), 4.36 (dd, J = 8.1, 6.7
Hz, 1 H), 4.51–4.62 (m, 2 H), 7.30 (d, J = 8.2 Hz, 2 H), 7.39 (ddd,
J = 7.7, 4.7, 1.1 Hz, 1 H), 7.72–7.79 (m, 3 H), 7.91–7.94 (m, 1 H),
8.68 (ddd, J = 4.9, 1.8, 0.9 Hz, 1 H).
13C{1H} NMR (125 MHz, CDCl3): δ = 21.7 (CH3), 65.5 (CH), 70.5
(CH2), 70.6 (CH2), 124.2 (CH), 126.1 (CH), 128.1 (2 CH), 130.0 (2
CH), 132.6 (C), 136.8 (CH), 145.2 (C), 146.1 (C), 150.0 (CH),
165.0 (C).
13C{1H} NMR (125 MHz, CD3OD): δ = 53.5 (CH2), 63.6 (CH), 65.5
(CH2), 123.5 (CH), 126.9 (CH), 138.2 (CH), 148.8 (C), 150.2 (CH),
165.5 (C).
HRMS (ESI, positive mode): m/z [M + H+] calcd for C9H12N3O:
178.0980; found: 178.0975.
Anal. Calcd for C9H11N3O (177.21): C, 61.00; H, 6.26; N, 23.71.
Found: C, 60.89; H, 6.57; N, 23.73.
(S)-1-(tert-Butoxycarbonyl)-4-(hydroxymethyl)-2-(2-pyridyl)-
4,5-dihydro-1H-imidazole (11)
K2CO3 (2.70 g, 19.5 mmol) and Boc2O (5.33 g, 24.4 mmol) were
added to a solution of compound 2 (1.73 g, 9.76 mmol) in H2O–
THF (30 mL, 1:3) and the resulting mixture was heated to reflux for
24 h. All volatile materials were then removed under reduced pres-
sure, the residue was partitioned between CH2Cl2 (100 mL) and
H2O (100 mL), the aqueous layer was extracted with CH2Cl2 (50
mL), and the combined organic layers were dried (MgSO4) and fil-
tered. The solvent was removed under reduced pressure to yield
compound 11 as a mixture with Boc2O (2.30 g) as crude material
(Boc2O/11, 1:3 by 1H NMR spectroscopy; i.e., 1.82 g, 6.57 mmol,
67%), which was used for the next step without further purification.
An analytically pure sample was obtained by column chromatogra-
phy (silica gel, 3 cm × 10 cm; EtOAc–MeOH, 5:1, Rf = 0.22) as a
light yellow oil.
HRMS (ESI, positive mode): m/z [M
+
Na+] calcd for
C16H16N2NaO4S: 355.0728; found: 355.0728.
Anal. Calcd for C16H16N2O4S (332.37): C, 57.82; H, 4.85; N, 8.43;
S, 9.65. Found: C, 57.91; H, 4.86; N, 8.47; S, 9.65.
(S)-4-(Azidomethyl)-2-(2-pyridyl)-4,5-dihydrooxazole (10)
NaN3 (3.39 g, 52.1 mmol) was added to a solution of compound 9
(3.46 g, 10.4 mmol) in EtOH (150 mL) and the resulting mixture
was heated to reflux for 16 h. After the solvent was removed, the
residue was partitioned between CH2Cl2 (100 mL) and H2O (100
mL), and the aqueous layer was extracted with CH2Cl2 (50 mL).
The combined organic layers were dried (MgSO4) and filtered, and
the solvent was removed under reduced pressure. The residue was
purified by column chromatography (silica gel, 5 cm × 10 cm;
EtOAc–hexane, 9:1, Rf = 0.15) to yield compound 10 (2.12 g, 10.4
mmol, 99%) as a light yellow oil.
[α]D20 +92.5 (c 0.46, CH2Cl2).
IR (ATR): 3312 (br), 2979 (w), 2932 (w), 2871 (w), 1708 (s), 1631
(m), 1588 (w), 1476 (w), 1365 (vs), 1286 (m), 1138 (vs), 1049 (w),
1025 (w), 917 (w), 729 (s) cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.21 (s, 9 H, 3 CH3), 3.64 (dd, J =
11.4, 5.0 Hz, 1 H, 4-CHH), 3.74 (dd, J = 11.4, 4.5 Hz, 1 H, 4-CHH),
3.84 (dd, J = 10.5, 8.0 Hz, 1 H, 5-H), 3.99 (t, J = 10.4 Hz, 1 H, 5-
H), 4.28 (ddt, J = 10.3, 8.1, 4.7 Hz, 1 H, 4-H), 7.29 (ddd, J = 7.7,
4.9, 1.1 Hz, 1 H, 5′-H), 7.47–7.50 (m, 1 H, 3′-H), 7.70 (td, J = 7.7,
1.7 Hz, 1 H, 4′-H), 8.58 (ddd, J = 4.9, 1.7, 1.1 Hz, 1 H, 6′-H).
13C{1H} NMR (125 MHz, CDCl3): δ = 27.8 (3 CH3, C(CH3)3), 49.3
(CH2, C-5), 64.3 (CH2, 4-CH2), 66.8 (CH, C-4), 81.9 (C, C(CH3)3),
123.4 (CH, C-3′), 124.3 (CH, C-5′), 136.3 (CH, C-4′), 148.8 (CH,
C-6′), 150.4 (C, C=O), 151.4 (C, C-2′), 159.4 (C, C-2).
[α]D20 –112.5 (c 1.01, CH2Cl2).
IR (ATR): 3057 (w), 2969 (w), 2902 (w), 2096 (vs), 1639 (m), 1581
(m), 1569 (m), 1516 (w), 1469 (m), 1440 (m), 1366 (m), 1258 (m),
1151 (w), 1102 (s), 1066 (m), 1043 (m), 994 (m), 965 (m), 931 (m),
905 (m), 856 (w), 800 (m) cm–1.
1H NMR (500 MHz, CDCl3): δ = 3.53–3.62 (m, 2 H), 4.33–4.41 (m,
1 H), 4.54–4.62 (m, 2 H), 7.42 (ddd, J = 7.6, 4.8, 1.0 Hz, 1 H), 7.80
(td, J = 7.8, 1.7 Hz, 1 H), 8.05 (dt, J = 7.9, 1.0 Hz, 1 H), 8.72 (ddd,
J = 4.8, 1.6, 1.0 Hz, 1 H).
15N NMR (HMBC, 50.7 MHz, CDCl3): δ = –74.1 (N-1′), –122.8 (N-
3), –244.5 (N-1).
13C{1H} NMR (125 MHz, CDCl3): δ = 54.2 (CH2), 66.5 (CH), 70.7
(CH2), 124.2 (CH), 125.9 (CH), 136.7 (CH), 146.2 (C), 149.9 (CH),
164.5 (C).
HRMS (ESI, positive mode): m/z [M
+
Na+] calcd for
C14H19N3NaO3: 300.1324; found: 300.1319.
Synthesis 2014, 46, 81–86
© Georg Thieme Verlag Stuttgart · New York

PAPER
Ring Transformation of a 4-(Aminomethyl)oxazoline
85
(S)-1-(tert-Butoxycarbonyl)-4-[(4-methylphenylsulfonyl-
oxy)methyl]-2-(2-pyridyl)-4,5-dihydro-1H-imidazole (12)
TsCl (7.23 g, 37.9 mmol) was added to a solution of crude com-
IR (ATR): 3333 (w), 3055 (w), 2976 (w), 2930 (w), 2867 (w), 1690
(s), 1607 (m), 1567 (m), 1494 (m), 1457 (m), 1421 (m), 1366 (s),
1273 (s), 1249 (s), 1163 (vs), 994 (w), 979 (w), 744 (w) cm–1.
1H NMR (500 MHz, CD3OD): δ = 1.33 (s, 9 H), 3.16–3.18 (m, 2 H),
3.57 (dd, J = 12.4, 7.2 Hz, 1 H), 3.84 (dd, J = 10.7, 7.1 Hz, 1 H),
4.14 (ddt, J = 10.9, 7.0, 5.7 Hz, 1 H), 7.42 (ddd, J = 7.6, 4.8, 1.1 Hz,
1 H), 7.53 (td, J = 7.7, 1.7 Hz, 1 H), 7.93 (dt, J = 7.9, 1.2 Hz, 1 H),
8.55 (ddd, J = 4.9, 1.6, 0.9 Hz, 1 H).
1
pound 11 (2.10 g, Boc2O/11, 1:3 by H NMR spectroscopy; i.e.,
1.66 g, 6.00 mmol) in 15% aq KOH solution (50 mL) and CH2Cl2
(50 mL), and the resulting mixture was heated to reflux for 3 h. The
layers were separated and the aqueous layer was extracted with
CH2Cl2 (50 mL). The combined organic layers were dried (MgSO4)
and filtered, and the solvent was removed under reduced pressure.
The residue was purified by column chromatography (silica gel, 5
cm × 10 cm; EtOAc–MeOH, 5:1, Rf = 0.23) to yield compound 12
(1.03 g, 2.39 mmol, 40%; 27% over two steps) as a yellow oil.
13C{1H} NMR (125 MHz, CD3OD): δ = 28.7 (3 CH3), 45.4 (CH2),
53.9 (CH2), 62.0 (CH), 80.2 (C), 123.7 (CH), 127.1 (CH), 138.3
(CH), 148.4 (C), 150.3 (CH), 158.7 (C), 165.6 (C).
[α]D20 +65.8 (c 0.25, CH2Cl2).
HRMS (ESI, positive mode): m/z [M + H+] calcd for C14H21N4O2:
277.1665; found: 277.1659.
IR (ATR): 2978 (w), 2931 (w), 2871 (w), 1708 (s), 1630 (w), 1588
(w), 1474 (w), 1365 (vs), 1288 (m), 1175 (vs), 1096 (m), 1049 (w),
982 (s), 950 (m), 815 (w), 790 (m), 665 (m), 554 (s) cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.21 (s, 9 H), 2.43 (s, 3 H), 3.81
(dd, J = 11.1, 7.2 Hz, 1 H), 3.99–4.13 (m, 2 H), 4.27 (dd, J = 9.9,
4.1 Hz, 1 H), 4.36–4.48 (m, 1 H), 7.29–7.37 (m, 3 H), 7.46 (dt, J =
8.0, 0.9 Hz, 1 H), 7.72 (td, J = 7.8, 1.8 Hz, 1 H), 7.77–7.81 (m, 2 H),
8.61 (ddd, J = 4.9, 1.5, 1.1 Hz, 1 H).
13C{1H} NMR (125 MHz, CDCl3): δ = 21.8 (CH3), 27.8 (3 CH3),
50.0 (CH2), 63.5 (CH), 70.9 (CH2), 82.4 (C), 123.4 (CH), 124.5
(CH), 128.2 (2 CH), 130.1 (2 CH), 132.6 (C), 136.4 (CH), 145.1
(C), 149.0 (CH), 150.2 (C), 151.1 (C), 160.5 (C).
Acknowledgment
We are grateful to Andre Appeldorn for his assistance in the labora-
tory.
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HRMS (ESI, positive mode): m/z [M
+
Na+] calcd for
C21H25N3NaO5S: 454.1413; found: 454.1403.
(S)-4-(Azidomethyl)-1-(tert-butoxycarbonyl)-2-(2-pyridyl)-4,5-
dihydro-1H-imidazole (13)
A solution of NaN3 (776 mg, 11.9 mmol) and compound 12 (1.03 g,
2.39 mmol) in EtOH (20 mL) was heated to reflux for 16 h. Then,
the solvent was removed under reduced pressure and the residue
was partitioned between CH2Cl2 (25 mL) and H2O (25 mL). The
aqueous layer was extracted with CH2Cl2 (25 mL), the combined or-
ganic layers were dried (MgSO4) and filtered, and the solvent was
removed under reduced pressure to yield compound 13 (530 mg,
1.75 mmol, 73%) as a yellow oil.
[α]D20 +95.6 (c 0.79, CH2Cl2).
IR (ATR): 2979 (w), 2932 (w), 2102 (s), 1711 (s), 1633 (w), 1587
(w), 1520 (w), 1472 (w), 1368 (vs), 1277 (m), 1259 (m), 1168 (m),
1142 (s), 997 (w), 982 (s) cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.20 (s, 9 H), 3.51 (dd, J = 12.4,
4.7 Hz, 1 H), 3.59 (dd, J = 12.4, 5.4 Hz, 1 H), 3.82 (dd, J = 10.9, 7.1
Hz, 1 H), 4.07 (t, J = 10.6 Hz, 1 H), 4.36–4.42 (m, 1 H), 7.33 (ddd,
J = 7.7, 4.8, 1.1 Hz, 1 H), 7.53 (dt, J = 7.7, 1.0 Hz, 1 H), 7.74 (td,
J = 7.7, 1.5 Hz, 1 H), 8.62 (ddd, J = 5.4, 1.5, 1.0 Hz, 1 H).
13C{1H} NMR (125 MHz, CDCl3): δ = 27.7 (3 CH3), 50.2 (CH2),
54.5 (CH2), 64.6 (CH), 82.1 (C), 123.2 (CH), 124.3 (CH), 136.3
(CH), 148.9 (CH), 150.3 (C), 151.4 (C), 159.9 (C).
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55, 5377.
HRMS (ESI, positive mode): m/z [M
+
Na+] calcd for
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C14H18N6NaO2: 325.1389; found: 325.1380.
(R)-4-(Aminomethyl)-1-(tert-butoxycarbonyl)-2-(2-pyridyl)-
4,5-dihydro-1H-imidazole (14)
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freeze, pump and thaw) and then stirred under an atmosphere of H2
(1 atm) for 16 h at 23 °C. The mixture was filtered, then the solvent
was removed under reduced pressure and the residue was purified
by column chromatography (silica gel, 3 cm × 5 cm; EtOAc–
MeOH, 5:1, Rf = 0.08) to yield compound 14 (126 mg, 0.46 mmol,
67%) as a colorless oil.
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 81–86

86
M. Schulz, J. Christoffers
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Synthesis 2014, 46, 81–86
© Georg Thieme Verlag Stuttgart · New York