Direct addition of 2-methylazines to aryl glyoxals for the synthesis of α-hydroxy ketones

Article abstract of DOI:10.1016/j.tetlet.2015.07.053

A catalyst-free protocol for the reaction of 2-methylazines and aryl glyoxal hydrates leading to α-hydroxy ketones bearing azaarene moiety is described. The process is operationally simple and can be applied to a broad range of substrates.

Full text of DOI:10.1016/j.tetlet.2015.07.053

Accepted Manuscript
Direct addition of 2-methylazines to aryl glyoxals for the synthesis of α-hydroxy
ketones
Binbin Li, Huiping Wei, Haiyan Li, Olga P. Pereshivko, Vsevolod A. Peshkov
PII:
S0040-4039(15)01206-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.07.053
TETL 46542
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
17 June 2015
12 July 2015
16 July 2015
Please cite this article as: Li, B., Wei, H., Li, H., Pereshivko, O.P., Peshkov, V.A., Direct addition of 2-methylazines
to aryl glyoxals for the synthesis of α-hydroxy ketones, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/
j.tetlet.2015.07.053
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Direct addition of 2-methylazines to aryl glyoxals for the synthesis of α-hydroxy
ketones
#
#
Binbin Li, Huiping Wei, Haiyan Li, Olga P. Pereshivko, Vsevolod A. Peshkov*
College of Chemistry, Chemical Engineering and Materials Science, Soochow University,
Dushu Lake Campus, Suzhou, 215123, China
#
These authors contributed equally to this work.
Email: vsevolod@suda.edu.cn
ABSTRACT. A catalyst-free protocol for the reaction of 2-methylazines and aryl glyoxal hydrates leading to α-
hydroxy ketones bearing azaarene moiety is described. The process is operationally simple and can be
applied to a broad range of substrates.
Keywords: 2-methylazines, aryl glyoxals, α-hydroxyketones, azaarenes
Modern organic synthesis strives for development of novel, sustainable and operationally simple procedures.
3
1
Many of recent efforts have been focused on the direct functionalization of ubiquitous C(sp )–H bond. In
2
3
4
this regard, the additions of 2-methylazines to carbonyl or imine groups as well as to other electrophiles
have recently emerged as an efficient and atom economic strategy to access various types of azaarene
containing building blocks. Typically, such transformations utilize catalytic amounts of Lewis or Brønsted acid
5
while some of very recent approaches are catalyst-free. Following the success of these procedures, we have
6
,7
developed a direct catalyst-free coupling of 2-methylazines 1 and aryl glyoxal hydrates 2 for the
straightforward synthesis of a wide range of α-hydroxyketones 3 bearing azaarene moiety. Herein we
present the scope and limitations of this process.
We started our investigation with a search for the optimal reaction parameters (Table 1). We chose
additions of 2-picoline (1a) and 2,6-lutidine (1b) to phenyl glyoxal hydrate (2a) as two model reactions.
Initially, we have found that 2a reacts with 1a (1.2 equiv.) at 110 °C in dioxane delivering α-hydroxyketone
3a in 21 % NMR yield which corresponds to 17 % isolated yield after column chromatography (Table 1, entry
1). Increasing the access of 1a up to 3 equiv. resulted in enhancement of NMR and isolated yields of 3a up to
49 % and 44 % respectively (Table 1, entry 2). Further variations in solvent, dilution, reagents ratio as well as

in reaction time and temperature did not provide an additional improvement (Table 1, entries 3-14). The
reaction of phenyl glyoxal hydrate (2a) with 2,6-lutidine (1b) that contain two reactive methyl groups (Table
1, entries 15-18) required only 2 equiv. of 1b to achieve a reasonable yield of α-hydroxyketone 3b (Table 1,
entry 17).
a
Table 1. Optimization of reaction parameters
b
c
d
Entry
R (1)
x
1.2
3
3
2
2
2
3
3
3
5
3
2
3
3
3
3
Solvent
dioxane
dioxane
toluene
dioxane
dioxane
toluene
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxaneb
Dilution, M
0.5
0.5 M
0.5 M
2
Temp, °C
110
110
110
110
110
110
110
110
110
110
110
110
140
90
Time, h Product (3) Yield
e
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
Me (1b)
Me (1b)
Me (1b)
Me (1b)
20
14
14
25
14
14
14
20
14
14
20
14
14
20
14
14
14
14
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
21 (17)
49 (44)
24
e
22
25
12
45
47
41
41
36
41
32
13
62
2
2
0.67 M
0.5 M
0.33 M
0.33 M
0.2 M
0.5 M
0.5 M
0.5 M
0.33 M
0.5 M
0.5 M
1
1
1
1
1
1
1
1
1
110
110
110
110
63
e
2
1.5
63 (62)
0.5 M
48
a
c
d
The reactions were run on 1 mmol scale. Based on 2a. This refers to the oil bath temperature. Yields are
determined by H NMR using 3,4,5-trimethoxybenzaldehyde as internal standard. Isolated yield is given in
parentheses.
1
e
8
Having these results in hand, we moved to the substrate scope evaluation (Table 2). At first, we studied
additions of various 2-methylazines 1a-h to phenyl glyoxal hydrate (2a) (Table 2, entries 1-8). 2,6-Lutidine
(
1b) showed a better performance compared to 2-picoline (1a) which could be ascribed to the presence of
two reactive methyl groups (Table 2, entry 2 versus entry 1). In contrast, 2,6-dimethylpyrazine (1c) delivered
α-hydroxyketone product 3c in only poor yield of 12 % (Table 2, entry 3). 2-Methylquinolines 1d-g and 1-
methylisoquinoline 1h reacted well delivering desired α-hydroxyketones 3d-h with the yields ranging from
37 to 55 % (Table 2, entries 4-8). For the reactions with substrates 1d and 1h, chalcone-type side products
4d and 4h were isolated in addition to the standard α-hydroxyketone products 3d and 3h (Table 2, entries 4
and 8). Next, we turned our attention to the reactions of various aryl glyoxal hydrates 2b-d in combination
with 2-methylazines 1a,b,d,e. All reactions were successful allowing to obtain diverse α-hydroxyketones 3i-q

in 31 to 65 % yield (Table 2, entries 9-18). It is important to stress that some of the reactions required higher
dilution and the use of reduced temperature of either 95 °C or 100 °C in order to avoid the formation of
minor quantities of 5-type side product resulting from the double addition of 2-methylazine 1 to aryl glyoxal
hydrate 2. Such side product, if formed, could not be separated from the corresponding desired product 3
by the column chromatography and, thus, hampers its isolation in pure form. However, in one case namely
for the reaction of 4-chloro-2-methylquinoline (1i) with phenyl glyoxal hydrate (2a) the double addition
product 5 was obtained as a major product and no α-hydroxyketone 3r was formed (Scheme 1).
a
Table 2. Scope of the process
d
Entry
1
x
Temp, Dilution,
1
2
Product (3)
Yield
44
b
c
°C
M
3
110
0.5
2
3
4
5
6
7
2
3
3
3
3
3
110
110
100
110
110
100
0.5
0.5
2a
2a
2a
2a
2a
2a
62
12
e
0.33
0.5
55 (20)
46
0.33
0.33
47
51
e
8
3
95
0.33
2a
37 (17)

9
3
110
0.5
1a
31
10
11
12
3
2
2
110
110
110
0.5
0.5
0.5
1a
1b
1b
46
58
52
2b
2c
1
3
4
2
4
35
38
110
0.5
1b
f
1
15
16
17
18
3
3
3
3
100
100
110
110
0.33
0.33
0.25
0.5
1d
1d
1e
1e
2b
2c
2b
2c
58
50
65
54
g
h
a
b
c
Unless otherwise stated all reactions were run on 1 mmol scale for 14 h. This refers to the oil bath temperature.
d
e
f
g
Based on 2. Isolated yields. The yield of side product 4 is given in parentheses. The reaction was run for 20 h. The
reaction was run on 0.5 mmol scale. The reaction was run on 0.6 mmol scale.
h
Scheme 1. Double addition of 4-chloro-2-methylquinoline (1i) to phenyl glyoxal hydrate (2a)

1
13
The obtained products 3a-q, 4d,h and 5 were characterized using H and C NMR spectroscopy and HRMS.
In addition, the structures of α-hydroxyketone 3l and the double addition product 5 were assured by X-ray
9
crystallographic analysis.
Figure 1. X-ray crystallographic structures of compounds 3l and 5.
In conclusion, we have demonstrated that the aryl glyoxal hydrates could be successfully used as an
electrophilic carbonyl component in the reactions with 2-methylazine nucleophiles. The developed catalyst-
free protocol allowed to prepare a small library of azaarene containing α-hydroxyketones in moderate yields.
Acknowledgements
This work was supported by the start-up fund from Soochow University (grant number Q410900714) and
the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).
Supplementary data
1
13
Full experimental procedures as well as copies of H and C NMR spectra of the compounds associated with
this article can be found, in the online version, at http://dx.doi.org/.

References and notes
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5
6
A previous attempt by Zhou, Uozumi and coworkers to react phenyl glyoxal (2a) with quinaldine (1d) in the
2
b
presence of Fe(OAc) (10 mol%) met with failure due to decomposition of 2a (see ref. ).
2
7. For a focused review about the application of aryl glyoxals in heterocyclic chemistry, see: Eftekhari-Sis, B.;
Zirak, M.; Akbari, A. Chem. Rev. 2013, 113, 2958−3043.
8. Representative procedure for additions of 2-methylazines 1 to aryl glyoxal hydrates 2 exemplified by the
synthesis of 2-hydroxy-1-phenyl-3-(pyridin-2-yl)propan-1-one (3a). Phenyl glyoxal hydrate (2a) (152 mg, 1
mmol) was placed into screw cap vial and dissolved in dioxane (2 ml) followed by addition of 2-picoline (1a)
(279 mg, 3 mmol). The reaction mixture was sealed and kept under stirring at 110 °C for 14 h. The resulting
mixture was diluted with DCM and evaporated with silica gel. Column chromatography with heptane-EtOAc
1
(
2050 %) delivered pure 3a (100 mg, 44 %). H NMR (400 MHz, CDCl
3
): δ 8.59-8.49 (m, 1H), 8.11-8.01 (m,
2
H), 7.66-7.56 (m, 2H), 7.55-7.44 (m, 2H), 7.23-7.11 (m, 2H), 5.55 (dd, J = 3.3, 8.5 Hz, 1H), 4.64 (bs, 1H), 3.36
1
3
(dd, J = 3.3, 14.5 Hz, 1H), 3.01 (dd, J = 8.5, 14.5 Hz, 1H); C NMR (100 MHz, CDCl ): δ 201.1, 158.1, 149.3,
3

+
1
36.7, 134.2, 133.9, 129.1, 128.9, 124.4, 121.9, 73.5, 43.0; HRMS (ESI, [M+H] ) for C14
H
14NO calcd. 228.1019,
2
found 228.1025.
9. CCDC 1406639 and 1406640 contains the supplementary crystallographic data for this paper and can be
obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html