N-Nitrosation of (E)-2-(benzylidene-amino)ethanols

Article abstract of DOI:10.1016/j.tetlet.2007.05.178

Reaction of (E)-2-(benzylidene-amino)ethanol 2 with nitric oxide afforded an (E)-rotamer dominant mixture of (E)- and (Z)-N-nitroso-2-aryl-1,3-oxazolidine 3 at room temperature in good overall yields.

Full text of DOI:10.1016/j.tetlet.2007.05.178

Tetrahedron Letters 48 (2007) 7418–7421
N-Nitrosation of (E)-2-(benzylidene-amino)ethanols
Li-jun Peng,a Zhong-quan Liu,b Jian-tao Wanga and Long-min Wua,*
aState Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, PR China
bInstitute of Organic Chemistry, Gannan Normal University, Ganzhou 341000, PR China
Received 9 May 2007; revised 28 May 2007; accepted 31 May 2007
Available online 6 June 2007
Abstract—Reaction of (E)-2-(benzylidene-amino)ethanol 2 with nitric oxide afforded an (E)-rotamer dominant mixture of (E)- and
(Z)-N-nitroso-2-aryl-1,3-oxazolidine 3 at room temperature in good overall yields.
Ó 2007 Published by Elsevier Ltd.
N-Nitroso compounds, in general, possess intriguing
properties with an impact on medicine and biochemis-
try.1 For example, they have been implicated in muta-
genesis and carcinogenesis, but have also been
successfully employed in enzyme inhibition and active
site mapping.2 The partial double bond character of
N–NO bond (Scheme 1) leads to the rotation around
N–NO bond to be restricted. As a result, an (E) and
(Z) conformational isomerization occurs.3
OH
H
CHO
HN
X
N
O
a
X
X
ring-2
1
chain-2
Scheme 2. Ring–chain tautomerism of 2. (a) 2-Aminoethanol, THF,
MgSO4, 1 h.
N-Nitrosamines have been prepared by various
approaches such as the nitrosation of amines by NaNO2
and an acid,4 the nucleophilic substitution of nitric oxide
(NO) or another nitroso compounds by a nitrogen anion
under a strong basic condition,5 or the acid-catalyzed
addition of HO–NO.3b Among them, the production
of N-nitroso-2-aryl-1,3-oxazolidines with a five-mem-
bered ring containing nitrogen and oxygen is particu-
larly of importance.4b N-nitroso-1,3-oxazolidine was
prepared from aminoethanol in the presence of excess
sodium nitrite in aqueous acidic solution, but in very
low yield.4b Indeed, 2-aryl-1,3-oxazolidines 2 can be eas-
ily accessible from benzaldehyde 1 (Scheme 2).6 Com-
pound 2 exists as a ring–chain tautomer of an imine,
(E)-2-(benzylidene-amino)ethanol, with a chain struc-
ture (chain-2) and a 2-aryl-1,3-oxazolidine with a five-
membered ring structure (ring-2) containing nitrogen
and oxygen atoms. Yet, ring-2 desired for the further
chemical manipulation is the minor species at equilib-
rium6a and both tautomers are unstable and decompose
in the presence of water. Therefore, the conversion of
chain-2 into stable monocyclic 3 (Scheme 3) is certainly
of significance.
As part of our ongoing research program on the chem-
istry of NO,7–11 we studied the reaction of NO with
compound 2. However, we had to address two issues
and these were (a) that NO led to the cleavage of
C@N bonds in Schiff bases,12 and (b) that the reaction
of NO with secondary amines afforded diazenium-1,2-
diolates.13 Hence, the nitrosation of amines was carried
out smoothly using NO in the absence of strong bases
such as KH.5
.
.
N
N
N
N
.
.
. .
.
.
O
.
O
.
.
.
Scheme 1. Resonance in N-nitrosamines.
In the present work, we will report our results on
the reaction of NO with tautomeric mixture 2. It
gave five-membered N,O-containing ring compounds,
N-nitroso-2-aryl-1,3-oxazolidines 3, as an (E)-structure
*
Corresponding author. Tel.: +86 931 891 2500; fax: +86 931 89155
57; e-mail addresses: penglj04@lzu.cn; nlaoc@lzu.edu.cn
0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.05.178

L. Peng et al. / Tetrahedron Letters 48 (2007) 7418–7421
7419
O
O
O
OH
H
N
N
CHO
N
N
N
O
X
a
b
X
X
X
2
1
E-3
Z-3
Overall yield up to 92%
Scheme 3. Reagents and conditions: (a) 2-Aminoethanol, THF, MgSO4, 1 h; (b) NO (trace O2), THF, 2 h.
dominant mixture of (E)- and (Z)-conformer (Scheme
3). In a representative experiment,14 treatment of
o-chlorobenzaldehyde (1b) with 2-aminoethanol and
MgSO4 in anhydrous tetrahydrofuran (THF) for 1 h
gave rise to a mixture of chain- and ring-2b (Scheme
3). Purified NO was then directly bubbled through the
above stirred solution at room temperature for ca. 2 h.
2-o-Chlorophenyl-N-nitroso-1,3-oxazolidine 3b was
obtained as a colorless crystal in 90% isolated yield
(Table 1). Its structure was characterized by 1H and
13C NMR, gHMQC, MS, HRMS, and X-ray crystallo-
graphy diffraction. Figure 1 shows 3b existing as a single
E-conformation in solid.15,3a Furthermore, X-ray
diffraction data indicate that O(1), N(1), N(2), C(7),
Table 1. Reaction of (E)-2-(benzylidene-amino)ethanol 2 with NO in
THF
Figure 1. Molecular structure of 3b.
Benzaldehyde
X
Yield
Chain-2/ Yield
(E)-3/
of 2 (%) ring-2a
of 3 (%) (Z)-3b
C(9), and C(8) lie almost on a plane except for O(2).
The bond length of N(1)–N(2) is given at 1.329 A, being
˚
1a
1b
1c
1d
1e
1f
H
98
96
98
94
98:2
95:5
94:6
82:18
88:12
90:10
96:4
85:15
88:12
95:5
88
90
90
92
83
85
88
90
91
90
89
84:16
86:14
82:18
76:24
84:16
86:14
85:15
77:23
78:22
84:16
82:18
o-Cl
p-Cl
p-NO2
p-OCH3 90
o-OCH3 92
p-CH3
m-NO2
o-NO2
o-CH3
m-Cl
shorter than a normal N–N single bond length of
1.449 A.16 These observations imply partial double bond
˚
character of the N–N(O) bond in 3b, in a manner similar
to the N–C(O) bond in amides,4c caused by the delocali-
zation of p-electrons on N@O bond onto the N–NO
bond through the conjugation interaction. It will largely
hinder the rotation of N–NO bond. Otherwise, the
phenyl moiety linked at C(7) is found to be perpendi-
cular with respect to the C(7)–N(2)–C(9)–C(8) plane.
In addition, two sets of 1H NMR peaks display 3b exist-
ing in solution as a mixture of two conformers, (E)-3b
and (Z)-3b.17
1g
1h
1i
98
96
95
97
97
1j
1k
96:4
a The ratio of chain-2 to ring-2 was evaluated using the characteristic
1H NMR peaks at 8.69–8.14 (N@CH) and 5.69–5.30 ppm (N–CH–
O).
b The ratio of (E)-3 to (Z)-3 was evaluated using the characteristic H
1
NMR peaks at 6.516–6.917 ((E)-3, N–CH–O) and 6.293–6.541 ppm
((Z)-3, N–CH–O).
A proposed mechanism for the N-nitrosation of 2 is
depicted in Scheme 4. It appears that a trace of O2
2 NO2
N2O3
2 NO + O2
NO2 + NO
O
O
O
N
N
OH
H
.
+
ON
.
N
N
N
N
O
O
O
H
ON
H
+ HNO2
-
O
O
X
N
X
X
X
3
ring-2
4
chain-2
Scheme 4.

7420
L. Peng et al. / Tetrahedron Letters 48 (2007) 7418–7421
Bn
Bn
(s)
(
s)
Bn
(
s
)
N
O
(s)
O
Bn
O
H
N
O
+
N
(s)
(R)
CHO
N
N
NH2
OH
HO
NO (trace O2)
THF, 0 oC, 2 h
MgSO4, THF, 1 h
Cl
Cl
Cl
99%
Cl
1%
1l
2l
(S, R)-3l
(S, S)-3l
Scheme 5.
retained in reaction system plays a key role in the initi-
ation of reactions under consideration. NO is readily
oxidized to NO2 and then converted into N2O3. Dis-
placement of the good leaving group nitrite (ꢀONO)
from N2O3 by the Lewis basic nitrogen of ring-2 leads
to form 4, which then undergoes a deprotonation to give
end product 3. Thus the process has the tendency to roll
the tautomerisation of 2 from chain-2 to ring-2.
Acknowledgment
Project 20572040 was supported by National Natural
Science Foundation of China.
References and notes
1. (a) White, E. H.; Darbeau, R. W.; Chen, Y.; Chen, D.;
Chen, S. J. Org. Chem. 1996, 61, 7986; (b) Darbeau, R.
W.; Gibble, R. E.; Pease, R. S.; Siso, L. M.; Heurtin, D. J.
J. Chem. Soc., Perkin Trans. 2 2001, 1084.
2. Ron, W. D.; Rebecca, S. P.; Edson, V. P. J. Org. Chem.
2002, 67, 2942.
3. (a) Karaghiosoff, K.; Klapo¨tke, T. M.; Mayer, P.;
Piotrowski, H.; Polborn, K.; Willer, R. L.; Weigand, J.
J. J. Org. Chem. 2006, 71, 1295; (b) Wu, H.; Loeppky, R.
N.; Glaser, R. J. Org. Chem. 2005, 70, 6790–6801.
4. (a) Butler, R. N.; Scott, F. L. J. Org. Chem. 1966, 3182; (b)
Saavedra, J. E. J. Org. Chem. 1981, 46, 2610; (c) Ohwada,
T.; Miura, M.; Tamaka, H.; Sakamoto, S.; Yamaguclin,
K.; Ikeda, H.; Inagaki, S. J. Am. Chem. Soc. 2001, 133,
10164.
Further study was carried out to extend the substrate
scope for chiral oxazolidines. As an example, N-nitroso-
2-(2S)-(40-chlorophenyl)-4-(4S)-4-benzyl-1,3-oxazolidine
3l was prepared using
a chiral 2-aminoethanol,
2-(2S)-amino-2-(40-chlorophenyl)ethanol, in a yield of
92% and a high diastereoselectivity (Scheme 5) with
the ratio of (S,S)-3l and (S,R)-3l up to 95/5 at room
temperature and up to 99/1 at 0 °C.18 Representatively,
the structure of (S,S)-3l (CCDC-630583) was established
by X-ray crystallography diffraction (Fig. 2).
In conclusion, an efficient approach to prepare (E)- and
(Z)-N-nitroso-2-aryl-1,3-oxazolidines has been devel-
oped herein. It offered advantages for a high diastereo-
selectivity in the preparation of N-nitroso-2-aryl-1,3-
oxazolidines.
5. Zhu, X. Q.; Xian, M.; Wang, K.; Cheng, J. P. J. Org.
Chem. 1999, 64, 4187.
6. (a) Fulop, F.; Mattinen, J. Tetrahedron 1990, 46, 6545; (b)
Lerestif, J. M.; Perrocheau, J. Tetrahedron 1995, 51, 6757.
As expected, these products were confirmed to be formed
as an equilibrium mixture of 2-aryl-1,3-oxazolidine and
imine which were identified by 1H NMR spectra. The
ratios of the former to latter ranged from 18:82 to 2:98
1
evaluated using H NMR peaks at 5.69–5.30 (N–CH–O)
and 8.69–8.14 ppm (N@CH). Ring–chain tautomers of 2-
aryl-1,3-oxazolidines were prepared by the reaction of the
corresponding aromatic aldehydes with an appropriate
amino alcohol in refluxing dry THF in the presence of
anhydrous MgSO4 for 1 h.
7. (a) Liu, Z. Q.; Li, R.; Yang, D. S.; Wu, L. M. Tetrahedron
Lett. 2004, 45, 1565; (b) Wu, W. T.; Liu, Q.; Shen, Y. L.;
Li, R.; Wu, L. M. Tetrahedron Lett. 2007, 48, 1653.
8. Liu, Z. Q.; Fan, Y.; Li, R.; Zhou, B.; Wu, L. M.
Tetrahedron Lett. 2005, 46, 1023.
9. Liu, Z. Q.; Zhou, B.; Liu, Z. L.; Wu, L. M. Tetrahedron
Lett. 2005, 46, 1096.
10. Yang, D. S.; Lei, L. D.; Liu, Z. Q.; Wu, L. M. Tetrahedron
Lett. 2003, 44, 7245.
11. Li, R.; Liu, Z. Q.; Zhou, Y. L.; Wu, L. M. Synlett 2006,
1367.
12. Hrabie, J. A.; Srinivasan, A.; George, C.; Keefer, L. K.
Tetrahedron Lett. 1998, 39, 5933.
13. Hrabie, J. A.; Klose, J. R. J. Org. Chem. 1993, 58,
1472.
Figure 2. Molecular structure of (S,S)-3l.

L. Peng et al. / Tetrahedron Letters 48 (2007) 7418–7421
7421
14. A representative procedure: treatment of 140 mg of o-
chlorobenzaldehyde 1b with 61 mg of 2-aminoethanol 1
and 360 mg of MgSO4 in 30 mL of anhydrous THF for 1 h
gave rise to a mixture of chain- and ring-2b. NO was
produced by the reaction of a 1 M H2SO4 solution with
saturated aqueous solution of NaNO2 under an argon
atmosphere. H2SO4 was added dropwise. NO was carried
by argon and purified by passing it through a series of
scrubbing flasks containing 4 M NaOH, distilled water,
and CaCl2 in this order. Purified NO was then bubbled
through the stock solution, stirred at room temperature
for ca. 2 h. The stock solution was kept at a pressure of up
to +10 mm H2O column over local atmospheric pressure
at 20 °C. After completion of the reaction, as indicated by
TLC, the mixture was concentrated under vaccum, puri-
fied by column chromatography on silica gel (200–300
mesh, ethyl acetate–petroleum ether), and recrystallized
from ethyl acetate, yielding colorless crystal 3b (190 mg,
90% yield). Compound 3b was characterized by 1H and
13C NMR, HMQC, MS, HRMS, and X-ray crystallogra-
phy diffraction. Data for 2-(2-chlorophenyl)-3-nitrosoox-
azolidine ((E)-3b, (Z)-3b): colorless crystal, mp 44.2 °C; IR
(KBr) mmax 3435.4 (vs), 3065.0 (vs), 2901.6 (s), 1410.3 (s),
1268.9 (s, msym NO) cmꢀ1; MS (EI, 70 eV) m/z 212 (M+,
28), 168 (100), 139 (38), 125 (63), 111 (28), 89 (66), 75 (52);
HMRS-ESI m/z calcd for C9H9N2O2Cl+Na 235.0244,
found 235.0245, error ꢀ0.6 ppm. (E)-3b: 1H NMR
(600 MHz, CDCl3) d 7.05–7.47 (m, 4H, –Ph-o-Cl), 6.92
(s, 1H, –N–CH–O), 4.38–4.42 (m, 1H, –O–CHe), 4.17–4.21
(m, 1H, –O–CHa), 3.96–4.00 (m, 1H, –N–CHe), 3.74–3.79
(m, 1H, –N–CHa); 13C NMR (150 MHz, CDCl3) d 134.25
(–Ph-o-Cl), 132.98 (–Ph-o-Cl), 131.13 (–Ph-o-Cl), 130.20
(–Ph-o-Cl), 128.68 (–Ph-o-Cl), 127.06 (–Ph-o-Cl), 88.66
(–N–CH–O), 64.84 (–O–CH2), 43.69 (–N–CH2). (Z)-3b:
1H NMR (600 MHz, CDCl3) d 7.05–7.47 (m, 4H, –Ph-o-Cl),
6.54 (s, 1H, –N–CH–O), 4.85–4.89 (m, 1H, –N–CHa),
4.51–4.55 (m, 1H, –N–CHe), 4.31–4.34 (m, 1H, –O–CHe),
4.15–4.21 (m, 1H, –O–CHa); 13C NMR (150 MHz,
CDCl3) d 133.38 (–Ph-o-Cl), 131.97 (–Ph-o-Cl), 130.60
(–Ph-o-Cl), 130.29 (–Ph-o-Cl), 127.67 (–Ph-o-Cl), 126.87
(–Ph-o-Cl), 87.74 (–N–CH–O), 65.38 (–O–CH2), 48.12
(–N–CH2). Crystal data for 3b: C9H9N2O2Cl,
Mr = 212.63, orthorhombic, space group P2(1)2(1)2(1)
˚
˚
with cell parameters: a = 6.6705(2) A, b = 10.9436(3) A,
˚
c = 13.3939(4) A, a = 90.00°, b = 90.00°, c = 90.00°,
3
q
calcd = 1.444 mg/m3, Z = 4, T =
˚
V = 977.75(5) A ,
273(2) K, l = 0.365 cmꢀ1
,
F0 0 0 = 440, ꢀ8 6 h 6 8,
ꢀ13 6 k 6 11, ꢀ16 6 l 6 16, 4.80° 6 2h 6 51.96°, 1921
data collected, 1537 unique data (Rint = 0.0335), 128
refined parameters. GOF(F2) = 1.044, R1 = 0.0434,
wR2 = 0.1196. The X-ray crystallographic structure of 3b
is shown in Figure 1. The crystallographic data have been
deposited at the Cambridge Crystallographic Data Centre
as supplementary publication No. CCDC-608039.
15. Looney, C. E.; Phillips, W. D.; Reilly, E. L. J. Am. Chem.
Soc. 1957, 79, 6136.
16. Ren, X. Y.; Liu, Z. Y. Struct. Chem. 2005, 6, 567.
17. The peaks at 6.917 and 3.964–4.004 as well as 3.742–
3.792 ppm are assigned to C(7)–H and C(9)–H of (E)-3b,
respectively, and those at 6.540 and 4.890–4.855 as well as
4.550–4.506 ppm, characterized by gHMQC, to C(7)–H
and C(9)–H of (Z)-3b, respectively. Compared with (Z)-
3b, C(7)–H of (E)-3b shows a downfield chemical shift,
whereas C(9)–H shows an upfield chemical shift.4b The
ratio of (E)-3b to (Z)-3b is estimated from the integral of
the peak at 6.917 and 6.540 ppm and indicates that (E)-3b
is the preferable conformation of 3b.
18. The dienantiomers were purified and isolated by column
chromatography on silica gel (200–300 mesh, ethyl
acetate–petroleum ether) and recrystallization from ethyl
acetate, yielding (S,S)-3l and (S,R)-3l as colorless crystals
in a yield of 91% and 1%, respectively. It was estimated
that (E)-(S,S)-3l:(Z)-(S,S)-3l = 59:41 and (E)-(S,R)-3l:(Z)-
(S,R)-3l = 51:49.