Nucleophilic substitution reactions of aminoalkylbenzotriazoles with ytterbium metal umpoled diaryl ketones

Article abstract of DOI:10.1016/S0040-4039(02)00235-6

The reaction of diaryl ketones such as benzophenone with aminoalkylbenzotriazoles in the presence of ytterbium metal at room temperature has been found to give 2-amino alcohols in good yields under mild and neutral conditions.

Full text of DOI:10.1016/S0040-4039(02)00235-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2251–2253
Nucleophilic substitution reactions of aminoalkylbenzotriazoles
with ytterbium metal umpoled diaryl ketones
Weike Su,a,* Bibo Yanga and Yongmin Zhangb
aCollege of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, PR China
bDepartment of Chemistry, Zhejiang University (Campus Xixi ), Hangzhou 310028, PR China
Received 15 November 2001; revised 24 January 2002; accepted 31 January 2002
Abstract—The reaction of diaryl ketones such as benzophenone with aminoalkylbenzotriazoles in the presence of ytterbium metal
at room temperature has been found to give 2-amino alcohols in good yields under mild and neutral conditions. © 2002 Elsevier
Science Ltd. All rights reserved.
Lanthanoid reagents, especially samarium reagents,
have been extensively utilized in organic synthesis
because of their unique properties.1 For example, the
strong reducing ability of low-valent lanthanoids allows
the easy reduction of many functional groups and
provides a convenient method for reductive car-
bonꢀcarbon bond formation.2 Oxophilicity and the
high coordination numbers of trivalent lanthanoids
have enabled them to act as new Lewis acids.3 How-
ever, studies on the applications of ytterbium metal in
organic synthesis are relatively few. Hou et al. have
reported that the carbonyl carbons of diaryl ketones
could be umpoled by the reaction with ytterbium metal
and the ytterbium–benzophenone dianionic complexes
thus formed were successfully characterized by X-ray
analyses.4 The anionic carbonyl carbons were nucle-
ophilic and were coupled with various electrophiles
such as ketones, nitriles, epoxides, carbon dioxide, etc.,5
to give the corresponding products (Scheme 1).
Here we wish to report the nucleophilic substitution
reaction of aminoalkylbenzotriazoles with ytterbium
metal umpoled diaryl ketones in which the carbonyl
groups are umpoled by ytterbium from electrophilic to
nucleophilic (Scheme 2). The results are shown in Table
1.
From Table 1, it can be seen that the substitution
pattern of the phenyl R2 strikingly affected the yields of
products 4. The yields for substrates without sub-
stituents and with substituents in a para-position were
much higher than those with the substituents in meta-
and ortho-positions (entries 1, 5, 6 and 7). Prolonged
reaction times and increased reaction temperatures
Scheme 1.
Scheme 2.
Keywords: ytterbium; nucleophilic substitution; aminoalkylbenzotriazoles.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00235-6

2252
W. Su et al. / Tetrahedron Letters 43 (2002) 2251–2253
Table 1. Ytterbium metal promoted reaction of diaryl ketones with aminoalkylbenzotriazoles6
Entry
Ar
R1
R2
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
p-MeC6H4
p-MeC6H4
p-ClC6H4
p-ClC6H4
H
H
Et
Et
H
H
H
C6H5
Et
C6H5
1
2
2
76 (3a)
68 (3b)
67 (3c)
65 (3d)
29 (3e)
Trace (3f)
Trace (3g)
71 (3h)
63 (3i)
21 (4a)
29 (4b)
28 (4c)
31 (4d)
68 (4e)
92 (4f)
94 (4g)
23 (4h)
32 (4i)
35 (4j)
20 (4k)
21 (4l)
p-MeOC6H4
p-ClC6H4
p-MeOC6H4
m-MeC6H4
o-EtC6H4
o-ClC6H4
C6H5
p-MeOC6H4
p-ClC6H4
p-ClC6H4
p-MeOC6H4
2
14
26
26
2
1
2
9
10
11
12
C6H5
Et
C6H5
62 (3j)
78 (3k)
76 (3l)
2
1
a Isolated yield based on aminoalkylbenzotriazoles.
O
Ar
Yb
THF-HMPA
r. t.
Ar
+
O
Yb
C
Ph
Ph
A
OYb
C
+
+
2
1
1
1
1
C HNHR
RCH NHR
Ar
R CH NHR
5
1
+
R
Ph
6
N
N
H2O
_
N
N
N
N
OH
C
2
CH
R
NH
2
C HNHR
Ar
1
R
1
Ph
R
3
Scheme 3.
scarcely improved the yields of products. Presumably
the increased steric hindrance prevented the nucle-
ophilic substitution.
described herein provides a useful method for the
preparation of 2-amino alcohols. Further studies to
develop other new reactions using the ytterbium–ben-
zophenone dianionic complexes (A) are now in
progress.
Aryl alkyl ketones and dialkyl ketones cannot be used
in this reaction because of the low stability of the
intermediates (A).7
Acknowledgements
The mechanism for the nucleophilic substitution reac-
tions of aminoalkylbenzotriazoles with ytterbium metal
umpoled diaryl ketones is not clear at present. Accord-
ing to Ref. 5b and considering benzotriazolyl as being
an excellent leaving group, a possible mechanism is
shown in Scheme 3. Aminoalkylbenzotriazoles have
been shown to exist in equilibrium with an iminium
cation in solution.8 Ytterbium metal reacts with ben-
zophenone to give the ytterbium–benzophenone dian-
ionic complexes (A). The complexes (A) acting as
nucleophilic reagents attack the electrophilic center of
the iminium cations 5 to generate the intermediates 6.
The corresponding amino alcohols 3 are obtained after
hydrolysis.
We are grateful to the center of engineering research of
Zhejiang University of Technology for financial help.
References
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In conclusion, with good yields, mild and neutral condi-
tions as well as a straightforward procedure, the work
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Takaki, K.; Taniguchi, Y. Shokubai 1995, 37, 211.

W. Su et al. / Tetrahedron Letters 43 (2002) 2251–2253
2253
4. (a) Hou, Z.; Takamine, K.; Fujiwara, Y.; Taniguchi, H.
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6. General procedure: In a 25 mL flask were placed Yb metal
powder (40 mesh, 1 mmol) and a magnetic stirring bar.
The flask was sealed with a serum cap. Pure and dry
nitrogen was then passed through and the metal was dried
by heating under a stream of nitrogen. One drop of methyl
iodide was added via a micro syringe and the metal was
heated slightly using a heat gun to activate the Yb metal.
Addition of THF (2 mL) gave a pale yellow slurry to
which HMPA (1 mL) was introduced. An appropriate
amount of diaryl ketone in THF (2 mL) was then added
and the solution immediately turned dark blue. The mix-
ture was then stirred at room temperature for a few
minutes and a purple solution was finally obtained, and
then aminoalkylbenzotriazoles 2 (1 mmol in THF, 2 mL)
was added. The mixture was stirred at room temperature
for the given time (see Table 1). The products were treated
with 0.1 M HCl (5 mL) and then extracted with diethyl
ether (3×30 mL). The combined organic extracts were
washed with brine and dried over anhydrous MgSO4.
After the solvent was evaporated under reduced pressure,
the crude products were purified by preparative TLC on
silica gel using ethyl acetate–cyclohexane (1:8) as eluent.
Compound 3a, oil. wmax/cm−1: 3504, 3401, 2866, 1602,
1503. lH: 6.60–7.51 (15H, m, ArH), 5.76 (2H, s, CH2), 3.86
(1H, s, OH), 3.29 (1H, br s, NH). MS (m/z,%): 290 (M++1,
19), 289 (M+, 4), 272 (23), 183 (10), 107 (63), 106 (100),
105 (43), 77 (38). Anal. C20H19NO. Calcd C, 83.04; H,
6.57; N, 4.84. Found C, 83.12; H, 6.51; N, 4.79%. Com-
pound 3j, mp 140–142°C. wmax/cm−1: 3550, 3429, 1670,
1175. lH: 6.26–7.55 (18H, m, ArH), 5.21 (1H, s, CH), 4.60
(1H, br s, OH), 2.90 (1H, s, NH), 2.30 (3H, s, CH3). MS
(m/z,%): 414 (M++1, 3), 396 (2), 218 (34), 217 (21), 216
(100), 138 (26), 111 (16), 105 (29), 91 (16), 77 (28). Anal.
C27H24ClNO. Calcd C, 78.26; H, 5.80; N, 3.38. Found C,
78.20; H, 5.71; N, 3.42%.
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