A free radical Mannich type reaction: selective α-CH aminomethylation of ethers by Ti(III)/t-BuOOH system under aqueous acidic conditions

Article abstract of DOI:10.1016/j.tet.2006.04.014

tert-Butoxy radical, generated by Ti(III)-one electron reduction of tert-butylhydroperoxide, selectively abstracts an α-H atom from ethers. The resulting α-ethereal radicals add to the C-atom of methylene iminium salts, formed in situ under aqueous acidic conditions, leading to a one-pot aminomethylation of ethers at room temperature. The aminoalkylation of ethers is also considered and the role of the metal ion is discussed.

Full text of DOI:10.1016/j.tet.2006.04.014

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Tetrahedron 62 (2006) 5986–5994
A free radical Mannich type reaction: selective a-CH
aminomethylation of ethers by Ti(III)/t-BuOOH system
under aqueous acidic conditions
Angelo Clerici,a Rosalba Cannella,a Nadia Pastori,a Walter Panzerib and Ombretta Portaa,
*
aDipartimento di Chimica, Materiali e Ingegneria Chimica ‘‘Giulio Natta’’, Politecnico di Milano, Via Mancinelli 7, 20131 Milano, Italy
bCNR Istituto di Chimica del Riconoscimento Molecolare, Sezione ‘‘A. Quilico’’, Via Mancinelli 7, 20131 Milano, Italy
Received 11 January 2006; revised 24 March 2006; accepted 6 April 2006
Available online 5 May 2006
Abstract—tert-Butoxy radical, generated by Ti(III)-one electron reduction of tert-butylhydroperoxide, selectively abstracts an a-H atom
from ethers. The resulting a-ethereal radicals add to the C-atom of methylene iminium salts, formed in situ under aqueous acidic conditions,
leading to a one-pot aminomethylation of ethers at room temperature. The aminoalkylation of ethers is also considered and the role of the
metal ion is discussed.
Ó 2006 Elsevier Ltd. All rights reserved.
(α-EWG) RH
1. Introduction
-
R2N
R2N
R(α EWG)
ionic
Cl-
NR2
H
+
H
The classical Mannich aminomethylation of R–H acidic sub-
strates is one of the most important carbon–carbon bond
forming reaction in organic chemistry.1 Aminomethylation
of nucleophilic radicals, formed by H-atom abstraction
from R–H substrates, would represent the radical version
of the classical Mannich reaction with the substantial differ-
ence such that the functional groups directly bonded to the
reactive carbon atoms in R–H must have opposite polarity.
HCl
+
R2NH
C
O
H2O
CH2
-
R(α EDG)
(α-EDG) RH
radical
Figure 1. Classical and radical-type Mannich reaction.
and nitrones.3–7 These substrates are less sensitive to hydro-
lysis than the former and show higher radical addition rates
due to extra-stabilisation in the addition transition state.9
Whereas electron-withdrawing groups (EWG) are suitable
for the ionic addition, electron-donor groups (EDG) favour
the nucleophilic radical addition to methylene-iminium
salts. As a consequence, the type of products accessible by
the classical and the radical-type Mannich reactions would
be complementary concerning the polarity of the substitu-
ents in b-position to the amino groups (Fig. 1).
Even more so, studies concerning intermolecular radical
addition to highly water-sensitive and easily polymerisable10
formaldehyde-imines and formaldehyde-iminium salts, gen-
erated in situ either in anhydrous organic solvents or in
aqueous co-solvents, have not attracted the organic chemists’
attention.
Recently,2–7 the carbon–nitrogen double bond has attracted
significant attention as an excellent acceptor of nucleophilic
radicals, however, only water-resistant imine derivatives
may be used in aqueous radical reactions.
We report here that the exceptional coordinative properties
of Ti(IV) make feasible the addition of a-ether radicals to
the C-atom of methylene iminium salts and formaldehyde-
imines formed in situ under aqueous conditions, leading to
a-aminomethylation of ethers in a free radical Mannich
type reaction (Fig. 1).
As a consequence, studies involving the reductive inter-
molecular radical addition to water-sensitive simple aldi-
mines are scattered2,8 in comparison to those dealing with
various C]N containing functional groups, such as oxime
ethers,glyoxylicoximeethers,N-sulfonylimines,hydrazones
2. Results and discussion
Our recent studies8d,e have shown that, under aqueous con-
ditions, a phenyl radical, generated by Ti(III)-induced
* Corresponding author. Tel.: +39 02 2399 3063; fax: +39 02 2399 3180;
e-mail: ombretta.porta@polimi.it
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.04.014

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A. Clerici et al. / Tetrahedron 62 (2006) 5986–5994
5987
CH3
CH3
decomposition of phenyldiazonium cation, abstracts either
an iodine-atom from alkyl iodides (Scheme 1, path a) or
an a-H atom from ethers (Scheme 1, path b), leading to a
one-pot addition of nucleophilic alkyl or a-alkoxyalkyl
radicals to the C-atom of aldimines, formed in situ and acti-
vated towards radical addition by Ti(IV)–N complexation.
NH
NH
NHCH3
2
1a
1b
NH2
1c
NHCH3
NH2
H
(R)Ar
H
OCH3
1e
C
O
+
N
1f
1d
H
Ar'
+
Figure 2. Representative amines 1a–f.
Ti(III) / PhN2
H2O, N2
(R)Ar
solution) to a homogeneous solution containing amine 1
(2 mmol), formaldehyde (7 mmol of a 40% aqueous solu-
tion) and TiCl3 (8 mmol, ca. 8 mL of a 15 wt % in 30 wt %
HCl solution) in 10 mL of glacial CH3COOH and 10 mL
of the ether 2 under investigation.12 The reaction can be
followed like a titration and it is over when the blue colour
of TiCl3 is completely discharged to give a homogeneous
yellow solution.
Ti(IV)
+
N
.
C
Ph
+
H
Ar'
(a)
(b)
R-I
THF
Ph-H
Ph-I
Under these conditions, we tested the reaction of a number of
representative amines 1a–f (Fig. 2) in the presence of either
THF (2a), 1,4-dioxane (2b) or Et2O (2c) as co-solvents.
H
N
H
H
(R)Ar
(R)Ar
N
Ar'
Ar'
(R)Ar
N
Ar'
+
O
Secondary aliphatic and aromatic amines 1a–d gave the
expected products 3a–k in fair to good isolated yields
(Table 1).
R
O
ca. 90:10
Scheme 1. Ti(III)/PhN+2 mediated radical addition to aldimines.
This one-pot three component reaction proved to be so clean
that with low boiling amines 1a–b, no chromatographic sep-
aration was required in order to obtain the spectroscopically
pure 1,2-aminoethers 3a–e (1H NMR purity of the crude
residue was ꢁ95%, entries 1–5). Pure 3f–k (entries 6–11)
were obtained after chromatographic separation from the
unreacted amines 1c–d.
Continuing our research on the manifold roles simulta-
neously played by Ti(III) and Ti(IV) ions in promoting tan-
dem radical one-pot multicomponent reactions, we report
here that the aqueous acidic TiCl3/t-BuOOH system is
a more practical, efficient and selective radical precursor
of a-alkoxyalkyl radicals from ethers11 than the previously
reported TiCl3/PhN+2 system8e and that even methylene imi-
nium salts and formaldehyde-imines may be successfully
used as radical acceptors. In fact, notwithstanding the aque-
ous medium, these species are formed in situ in an adequate
concentration to make the subsequent addition of a-ether
radicals preparatively advantageous for the synthesis of
1,2-aminoethers 3.
When p-methoxyaniline 1e (PMP–NH2) was used, as a rep-
resentative primary aromatic amine,13 under the reaction
conditions adopted for secondary amines (e.g., molar ratio
1e/HCHO, 1:3.5), the reaction went on and bis-adducts 4l–n
were obtained in addition to the desired products 3l–n
(Table 2, entries 1, 3 and 5).
However it was possible to control the selective formation of
3l–n by decreasing the amount of formaldehyde to 0.5 equiv
(Table 2, entries 2, 4 and 6). The use of 3l–n, as a starting
amine component under the conditions developed for sec-
ondary amines, led to bis-derivatives 4l–n in ca. 70% iso-
lated yields. The primary aliphatic amine 1f, under all the
experimental conditions tested, gave only the bis-adduct
4p (Table 2, entry 7).
According to the stoichiometry of Scheme 2, the Ti(III)/
t-BuOOH system readily assembles, in 30 min at room tem-
perature, an amine 1, formaldehyde and an ether 2 leading
to 3.
H
H
R
+
+ tert-BuOOH + 2 Ti(III)
+
+ 2 H
+
C
NH
R'
H
O
2a-c
O
1a-f
It should be underlined that the product arising from the
addition of b-THF radical (Scheme 1) to the C-atom of the
iminewas not obtained in everycase, showing that the Ti(III)/
t-BuOOH system is more selective than Ti(III)/PhN+2 in
abstracting a H-atom from THF.
R
N
+
+
2 Ti(IV)
H2O
tert-BuOH + 2
O
R'
3a-p
Scheme 2. Ti(III)/t-BuOOH mediated a-aminomethylation of ethers.
After a survey to optimise the reaction conditions, we found
that the reaction rapidly occurs at 20 ꢀC by dropwise addi-
tion (30 min) of t-BuOOH (4 mmol of a 80% aqueous
To extend the scope of the reaction from aminomethyla-
tion to aminoalkylation and aminoarylation of ethers, we
checked the applicability of the method to acetaldehyde,

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A. Clerici et al. / Tetrahedron 62 (2006) 5986–5994
Table 1. Mannich radical-type addition of ethers 2a–c to in situ generated
Table 2. Mannich radical-type addition of ethers 2a–c to an equilibrium
mixture of PMP–NH2 (1e) and formaldehyde under different experimental
conditions
methylene iminium saltsa
R'
+
R
R
H
tert-BuOOH/Ti(III)
H
+
H
H
H
N
tert-BuOOH/Ti(III)
H2O, H+, rt
N
C
H2O, H+, rt
O
PMP NH2
+
O
C
O
+
R'
H
O
H
O
1a-d
2a-c
3a-k
1e
2a-c
3 yield %b
3a: 88
H
Entry
1
Product
PMP N
4l-n
+
PMP N
O
2
O
N
3l-n
O
Entry
Product; yield %a
O
O
H
N
2
3b: 65
N
PMP
N
PMP
PMP
1b
2c
O
2
2
O
3l (30)
4l (34)
4l (6)
N
3
4
3c: 40
3d: 55
O
3l 68 (80)
O
O
H
N
N
N
PMP
N
3b
O
O
O
O
4m (24)
3m (41)
4c
5b
3m 70 (86)
4m (5)
5
6
7
3e: 55
O
H
PMP
Ph
N
PMP
N
O
O
2
Ph
N
N
3f: 60 (65)
3g: 75 (81)
4n (30)
4n (6)
O
3n (36)
6c
7d
3n 68 (80)
O
O
O
O
Ph
N
2
4p (30)
Ph
N
8
9
3h: 54 (63)
3i: 70 (81)
O
a,b
See footnotes a and b of Table 1, respectively.
c
Molar ratio of 1e/HCHO/t-BuOOH:Ti(III) was 1:0.5:2:4; yields are based
on the starting HCHO.
Benzylamine 1f was used; molar ratio of 1f/HCHO was 1:0.5.
N
N
d
Ph
Ph
O
O
tions, the Ti(III)/PhN+2 method (B) and the yields of 3t–v are
also compared with those reported by Tomioka8c in a three
component reaction with the use of dimethylzinc as a radical
initiator (C).
10
3j: 70 (84)
3k: 50 (65)
O
11
N
Ph
O
The comparison makes it clear that the method reported
herein is more practical, convenient and versatile than the
a
Molar ratio of 1:HCHO:t-BuOOH:Ti(III) was 1:3.5:2:4.
b
Isolated yields are based on the starting amine 1 (2 mmol); yields in
brackets have been determined by 1H NMR with an appropriate internal
standard added to the crude reaction mixture; yield of 3, based on the
converted 1, were always >90%.
Table 3. Addition of THF to an equilibrium mixture of PMP–NH2 (1e) and
aldehydes (R–CHO) by using different radical initiators
Product 3
Molar ratio
R–CHO/1e
Radical initiator,a 3 yield %b
p-bromobenzaldehyde,p-tolualdehyde,p-anisaldehyde,benz-
aldehyde and cyclohexylaldehyde, but of all the amines
screened (Fig. 2) only the primary aromatic amine 1e gave
the desired THF-adducts 3q–v (Table 3) as a 1:1 mixture
of diastereomers with no traces of bis-adduct 4.
A (30 min) B (3 h) C (time)
H
PMP
N
O
R
R¼H, 3l
R¼CH3, 3q
1:1
2:1
72
58
—
—
—
—
80 (90)c
63 (70)c
74 (85)c
80 (89)c
70 (79)c
80 (95)c
55+9d
55+7d
47+8d
The fact that any attempt to apply this radical addition to
in situ generated alkylidene or arylidene iminium ions proved
to be unsuccessful implies that steric factors are relevant to
the course of the reaction, as they are for the classical
Mannich reaction.
R¼p-Br-C6H4, 3r
1:1.5
R¼p-CH3-C6H4, 3s 1:1.5
R¼p-OCH3C6H4, 3t 1:1.5
57 (45 h)
74 (22 h)
44 (138 h)
R¼C6H5, 3u
1:1.5
2:1
51+9d
64
R¼cyclohexyl, 3v
A: Ti(III)/t-BuOOH (this work); B: Ti(III)/PhN+2 (Ref. 8e); C: Me2Zn/air
(Ref. 8c).
Isolated yields.
a
In Table 3, the yields of 3l and 3q–v, obtained with the
present method (A), are compared with those previously
obtained8e by using, under comparable experimental condi-
b
c
d
1H NMR yields with an appropriate internal standard.
b-THF adduct.

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A. Clerici et al. / Tetrahedron 62 (2006) 5986–5994
5989
other routes in a number of ways: shorter reaction times,
titration-like reaction, cheaper and easier to handle radical
source and higher-yielding reaction with wide applicability.
preparing the aldehyde for reaction with the amine (iii), and
that the transfer of the oxygen atom from the carbon to
Ti(IV) makes equilibrium iv less unfavourable.
2.1. Mechanistic considerations
The fast17 and irreversible step v further contributes to shift
the total equilibrium to the side of product, rendering the
process preparatively advantageous with either formalde-
hyde, aliphatic or aromatic aldehydes.
The sequence of steps i–vi reported in Scheme 3 would
represent a reasonable rationale of the reaction. The one-
electron reduction of t-BuOOH by Ti(III) ion gives the
tert-butoxy radical (i) which selectively abstracts an a-H
atom from the ether generating an a-ethereal radical (ii).
Finally, it must be pointed out that, in sharp contrast with the
substituent effects found in acid-catalysed condensation of
aromatic amines with aromatic aldehydes,18 the yields of
3s,t are higher than those of 3r and 3u (Table 3); however,
this experimental finding strongly supports the rationale of
Scheme 3.
i
.
+
tert-BuOOH +
tert-BuO
+
Ti(IV)
Ti(III) +
H2O +
H
ii
.
tert-BuO
+
tert-BuOH
+
.
H
O
O
Under our conditions, an electron-releasing group on the
aromatic ring of the aldehyde would increase the equilibrium
concentration of the Ti(IV)-complexed aldehyde and would
favour the Ti(IV)-assisted loss of water from the intermedi-
ate hemiaminal (Scheme 3, paths iii and iv, ArCHO instead
of HCHO).
R
N
R'
R
N
H2C
R'
R
N
R'
H
C
O
H
-
+
iii
H2O, HCl
Cl-
CH2
+
iv
+
+
Ti(IV)
+
H2O
H
IV
IV
OH(Ti
)
Ti
A
v
.
N
+
R
R'
A
+
+
CH2
Beside, the increased basic strength of the imine, brought
about by an electron-donor substituent on the aldehyde,19
would increase the equilibrium concentration of the Ti(IV)-
complexed imine, which is the reactive counterpart of the
incoming nucleophilic radical (Scheme 1).
.
O
+
O
B
vi
R
R'
Ti(IV)
B
Ti(III)
N
CH2
O
3
Scheme 3. Mechanistic rationale.
3. Conclusions
Owing to its nucleophilic character, the a-ethereal radical
adds to the C-atom of the methylene iminium salt A (v)
(or to the C-atom of the Ti(IV)-complexed imine) formed
in situ by a series of equilibrium reactions (iii, iv). The result-
ing electrophilic aminium radical B is then readily reduced
(vi) to the final product 3 by a second equivalent of Ti(III).
The success of this one-pot reaction is mainly due to the mul-
tiple role played by titanium, which in its lower oxidation
state acts both as a radical initiator and as a radical termina-
tor, while in its higher oxidation state acts as a Lewis acid
and dehydrating agent providing a relatively high concentra-
tion of the iminium salts (or of complexed aldimines), even
under aqueous conditions.
The H-atom abstraction from ethers by tert-butoxy radical
(i) is a fast process14 due to a favourable enthalpy balance,15
and to polar effects, but the series of equilibria involved in
the formation of A under aqueous conditions16 (iii, iv)
should be by far shifted to the left. In fact, for the conditions
under which the classical Mannich reaction is most com-
monly performed (aqueous formaldehyde solution), elevated
temperature and long reaction time are necessary for gener-
ation of a sufficient concentration of A.
Despite the simplicity of 1,2-aminoethers moiety, the syn-
thesis of these compounds is often difficult20,21and this new
method provides an easy entry to both N-aryl21 and N-alkyl
aminoethers starting from cheap and readily available re-
agents under very mild reaction conditions. Further studies
are currently under investigation with the aim to extend
the aminomethylation and aminoalkylation reaction to other
nucleophilic radicals.
In the modern variant of the Mannich reaction the methylene
iminium ion, rather than being generated under equilibrium
conditions, is separately preformed upon exclusion of mois-
ture or generated in situ starting from iminium ion equiva-
lents that permit an aprotic solvent to be used under milder
reaction conditions and shorter reaction time.1
4. Experimental
4.1. General
All reactions were performed under N2 at room temperature
1
In view of this, the salient feature of the present radical
Mannich type reaction is that aminoethers 3 are formed in
good yields at room temperature in ca. 30 min, notwith-
standing the aqueous medium (volume ratio H2O/ether/
CH3COOH, ca. 1:1:1).
(20 ꢀC). NMR spectra were recorded at 400 MHz for H
and 100 MHz for 13C, measured in CDCl3 and chemical
shifts were presented in parts per million (d). The follow-
ing aqueous solutions were used: 37% solution of formalde-
hyde (Aldrich); 80% solution of tert-butylhydroperoxide
(Fluka); 15% solution TiCl3 (C. Erba). Flash column chro-
matography was performed by using 40–63 mm silica gel
packing. Silica gel 60 F254 (1 mm) plates were used for PLC.
A plausible explanation is that Ti(IV) ion, owing to its
high oxophilicity, coordinates the carbonyl oxygen, thereby