Regioselective mannich reaction of phenols under high pressure using dichloromethane as C1 unit

Article abstract of DOI:10.3987/COM-08-S(N)111

Regioselectivity in Mannich reaction of 4-, 3-, and 2-substituted phenols with typical heterocyclic amines are investigated under reaction conditions developed by us. Phenol and 4-alkyl, and 4-chlorophenols in the title reaction predominantly gave the corresponding 2-(aminomethyl)phenols, while 4-methoxyphenol afforded, in addition to the mono(aminomethyl)phenols, a considerable amount of the bis adducts. Peculiarly enough, 3-methylphenol with amines afforded 3-methyl-4-(aminomethyl)phenols whereas 2-methylphenol produced 2-methyl-6-(aminomethyl)phenols.

Full text of DOI:10.3987/COM-08-S(N)111

HETEROCYCLES, Vol. 76, No. 2, 2008
1061
HETEROCYCLES, Vol. 76, No. 2, 2008, pp. 1061 - 1067. © The Japan Institute of Heterocyclic Chemistry
Received, 7th May, 2008, Accepted, 7th July, 2008, Published online, 10th July, 2008. COM-08-S(N)111
REGIOSELECTIVE MANNICH REACTION OF PHENOLS UNDER
HIGH PRESSURE USING DICHLOROMETHANE AS C1 UNIT#
Kiyoshi Matsumoto,1,2* Kouta Joho,2 Seisuke Mimori,2 Hirokazu Iida,2*
Hiroshi Hamana,2 and Akikazu Kakehi3
1
Elm Institute of Science, Hiei-dira 2-32-36, Otsu 520-0016, Japan (e-mail:
2
Kiyoshi.Matsumoto@ma1.seikyou.ne.jp), Faculty of Pharmacy, Chiba Institute
3
of Science, Choshi, Chiba 288-0025,
University, Nagano 380-8553, Japan
Faculty of Engineering, Shinshu
Abstract – Regioselectivity in Mannich reaction of 4-, 3-, and 2-substituted
phenols with typical heterocyclic amines are investigated under reaction
conditions developed by us. Phenol and 4-alkyl, and 4-chlorophenols in the title
reaction predominantly gave the corresponding 2-(aminomethyl)phenols, while 4-
methoxyphenol afforded, in addition to the mono(aminomethyl)phenols, a
considerable amount of the bis adducts. Peculiarly enough, 3-methylphenol with
amines afforded 3-methyl-4-(aminomethyl)phenols whereas 2-methylphenol
produced 2-methyl-6-(aminomethyl)phenols.
The Mannich reaction can be used to yield a variety of amino methyl derivatives (Mannich bases) which
have many synthetic and pharmacological applications.1 The reaction is general for most aldehydes and
ketones that have at least one enolizable hydrogen. More recently, an asymmetric version of Mannich
reactions promoted both by metal-based and metal-free asymmetric catalysts has attracted much attention
and has been developed because the chiral Mannich bases often have served as useful intermediates in the
synthesis of diverse biologically intriguing compounds such as alkaloids.2,3 However, there are only few
examples of Mannich reactions with phenols, particularly with respect to regiospecific aspects of the
reaction. Recently, a series of tridentate ligands, N-benzyl-2-(2-hydroxyphenyl)glycines were prepared by
the Mannich reactions of p-substituted phenols.4,5 As a matter of course, when the two ortho positions of
the phenol were blocked, as in the case of 2,6-dimethylphenol, the corresponding p-substituted
compounds were formed.

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HETEROCYCLES, Vol. 76, No. 2, 2008
One of the authors invented a novel and new method for Mannich reaction of simple aldehydes and
ketones employing CH2Cl2 as a C1 Unit.6 This methodology was also amenable to indoles that can be
used to develop Ifenprodil analogues (typical examples of cerebral infarction aftereffects treatment
medicines) as shown in Scheme 1.7 Below, we briefly report the results of regioselectivitiy in the title
Mannich reaction.
OH
N
Me
Ifenprodil
H
N
R2
R1
CH2Cl2
R1
+
R2
NH
N
P
N
H
R3
Scheme 1
In a typical example, a mixture of phenol (5 mmol), amine (15 mmol) and dichloromethane (10 mmol)
was diluted with methanol in an 8 mL polytetrafluoroethylene tube and compressed to 0.8 GPa and
o
heated to ca. 50 C for 4-8 days. The reaction conditions were optimized in the previous reported
reactions so that either 0.8 GPa or 0.6 GPa at 50 oC proved to be for choice of best, including the substrate
and reagents mol ratios.6,7
As representative heterocyclic amines, pyrrolidine, piperidine, morpholine, and thiomorpholine were
employed. The results of a variety of 4-substituted phenols with cyclic amines are summarized in Table 1.
Firstly, reaction of phenol (1a) with amines (2a-d) underwent regiospecific 2-aminomethylation to afford
chemo- and regioselectively the corresponding mono(aminomethyl) analogues (3ab-3ad) albeit in low
yields. It should be noted that the conventional Mannich reaction using formaldehyde generally gave the
2,6-bis(aminomethyl) derivatives.1
In the case of 4-methylphenol (1b) with amines (2a-c), higher yields of the corresponding
mono(aminomethyl) analogues (3ba-3bc) were obtained probably because of + I effect of methyl group.
The reaction with thiomorphorine (2d) gave also the desired product (4bd: 60%) along with the
bis(aminomethyl) product in 11 %. The reaction of t-butylphenol (1c) with 2a-b analogously reacted in
almost similar regioselective fashion.
In contrast, the activated 4-methoxyphenol (1d) afforded the mono(aminomethyl)phenols (3da-3dd)
along with a considerable amount of the bis(aminomethyl)phenols, being in agreement with the known
reactivity-selectivity principle.8

HETEROCYCLES, Vol. 76, No. 2, 2008
1063
4-Chlorophenols (1e) also smoothly underwent reaction to give predominantly the corresponding
(aminomethyl)phenols (3ea-3ed) rather than the bis(aminomethyl)phenols.
OH
OH
OH
CH2NR1R2
R2R1NH2C
CH2NR1R2
0.8 GPa
50 oC
4 d
CH2Cl2
R1R2NH
+
+
+
R
R
R
1a: R=H
1b: R=Me
2a: pyrrolidine
2b: piperidine
4aa - 4ed
3aa - 3ed
1c: R=t-Bu
1d: R=MeO
1e: R=Cl
2c: morpholine
2d: thiomorpholine
Scheme 2
Table 1. Mannich bases (3aa-4ed) from p-substituted phenols (1a-e), dichloromethane, and amines
(2a-d)a
Phenol Amine Pressure [Temp] Time Product
Yield
(%)b
Mp
(GPa) (oC)
(day)
(oC)c
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1c
1d
1d
1d
1d
1e
1e
1e
1e
2a
2b
2c
2d
2a
2b
2c
2d
2a
2b
2c
2d
2a
2b
2c
2d
2a
2b
2c
2d
0.6
0.6
0.8
0.8
0.5
0.5
0.5
0.6
0.8
0.8
0.8
0.8
0.8
0.8
0.8
0.8
0.8
0.8
0.8
0.8
[50]
[50]
[rt]
4
4
3
3
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
3aa
3ab
3ac
3ad
3ba
3bb
3bc
14
17
25
19
48
47
32
oil9
32-33 [lit., 30-32]10
93-94 [lit., 90]11
117-11812
[rt]
[50]
[50]
[50]
[50]
[50]
[50]
[50]
[50]
[50]
[50]
[50]
[50]
[50]
[50]
[50]
[50]
62-6312
56-57 [lit., 45]13
55-5714
3bd (4bd) 60 (11) 87-8812 (116.5-117)
3ca
3cb
3cc (4cc)
56
62
63 (7)
oil
50 [lit., 46-47]15
59.5 [lit., 76-78]15 (127-127.5)
3cd (4cd) 60 (11) 87-88 [85-87]16 (116.5-117)
3da (4da) 12 (36) oil (oil)
3db (4db) 53 (21) oil18 (oil)
3dc (4dc) 20 (20) oil17 (87-88)
3dd (4dd) 47 (29) 105.5-106.5 [102-104]18 (syrup)
3ea (4ea) 49 (15) 74-7519 (oil)
3eb
3ec (4ec)
35
36 (18) 73-7421 (oil)
55-56 [lit., 57]20
3ed (4ed) 73 (10) 131-133 [lit., 127-129]22 (120-121)
a Satisfactory spectroscopic and elemental analyses were obtained for all compounds.
b Isolated yield. Parenthesis shows the yields of the bis(aminomethyl) derivatives.
c Parenthesis shows mp of the bis(aminomethyl) derivatives.
The regioselective trends of the results are qualitatively in agreement with those of classical conventional
SEAr reactions because the 4 position is already blocked by a functional group.

1064
HETEROCYCLES, Vol. 76, No. 2, 2008
3-Methylphenol (5), which is not blocked at para-position, also underwent smooth reaction to afford the
corresponding 4-(aminomethyl)-3-methylphenol (6) in moderate isolated yields as summarized in Table 2.
No di(aminomethyl) analogues were not detected. The para-regioselectiviy is apparently ascribed to +M
effect of OH group.
OH
OH
R1R2NH
CH2Cl2 / MeOH
0.8 GPa, 50 oC, 4d
+
Me
Me
R1
2a: pyrrolidine
2b: piperidine
2c: morpholine
5
N
R2
6a - 6d
2d: thiomorpholine
OH
OH
OH
Me
R1
Me
R1
R2
Me
R1R2NH
CH2Cl2 / MeOH
0.8 GPa, 50 oC, 4d
N
+
N
R2
+
2a: pyrrolidine
2b: piperidine
2c: morpholine
7
R1
R2
8a-d
N
2d: thiomorpholine
9a-d
Scheme 3
Table 2. Mannich bases (6a-d, 8a-d, 9d) from m- and o-methylphenols (5, 7), dichloromethane, and
amines (2a-d)a
meta
ortho
Phenol Amine Product Yield
(%)b
Phenol Amine Product Yield Mp
Mp
(oC)c
(%)
(oC)
5
5
5
5
2a
2b
2c
2d
6a
6b
6c
6d
46 107-108d, 23
7
7
7
7
2a
2b
2c
8a
8b
8c
29
25
33
oil
16
27
oil24
oil
oil24
oil25
25 67.5-68.5d
2d 8d (9d)
30 (6) 76-77 (154.5-155.0)d
a
o
Reaction conditions were 0.8 GPa, 50 C and 4days. Satisfactory spectroscopic and elemental analyses
were obtained for all compounds.
b Isolated yield. Parenthesis shows the yields of the bis(aminomethyl) analogues.
c Parenthesis shows mp of the bis(aminomethyl) analogues.
d The structure was established by an X-ray analysis.
In contrast with this and very intriguingly enough, 2-methylphenol produced the
2-(aminomethyl)-6-methylphenol (8) in spite of strong +M effect of para-OH group together so-called
with buttressing effect. Only in the case of thiomorphorine, the 1,3-dimethylamino-5-methylphenol was
isolated in 6 % yield. The reason(s) for regiospecific aspects regarding 2-methylphenol and
3-methylphenol is (are) not yet clear.

HETEROCYCLES, Vol. 76, No. 2, 2008
1065
It is generally thought that the Mannich reaction takes place by electrophilic attack of a
methyleneimminium ion (10) which is presumably generated as depicted in Schemes 4 and 5.1
Further studies on applications of this methodology for synthetic applications to bidentate, tridentate and
calixarene ligands as well as theoretical calculations of regioselectivities are envisaged.
R1
R2
H
R1
R2
R1
R2
-Cl-
R1
+
Cl-
H
N
Cl
C
H
Cl
Cl CH2
N
N
H2C
NH
N
10
NH
+
R2
R1
R1
R2
R1
R2
-
R2
N
CH2
Scheme 4
O-
O
OH
O
R1
CH2NR1R2
H
+
-
H2C
N
CH2NR1R2
R2
Scheme 5
Note added in proof: Effect of pressure on the yield.
Table 3. Mannich bases (3ac and 3bc) from p-substituted phenols (1a or 1b),
dichloromethane, and 2c
Phenol Amine Pressure [Temp] Time Product
Yield
(%)
(GPa) (oC)
(day)
1a
1a
1a
1b
1b
2c
2c
2c
2c
2c
0.2
0.4
0.8
0.2
0.5
[rt]
[rt]
[rt]
[rt]
[50]
3
3
3
3
4
3ac
3ac
3ac
3bc
3bc
No reactions
13
25
No reactions
32
ACKNOWLEDGEMENTS
Financial supports from Chiba Institute of Science (Special Education and Research Grants in 2004, 2006,
and 2007 to KM, HI, and KM, respectively) are greatly acknowledged. Thanks are also extended to Dr.
Takane Uchida (Faculty of Education, Fukui University) for helpful discussions and to Mr. Shiro
Hashimoto and Mr. Yukio Ikemi (Graduate School of Human and Environmental Studies, Kyoto
University) for technical assistance in the initial stage of the present work.

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HETEROCYCLES, Vol. 76, No. 2, 2008
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