Solvent- and catalyst-free selective Mannich reaction on catechols and para substituted phenols: A convenient route to catechol- and phenol-iminodiacetic acid ligands

Article abstract of DOI:10.1081/SCC-200034816

We have developed a convenient solvent- and catalyst-free selective Mannich reaction of a variety of para-substituted phenols or catechols with paraformaldehyde and ethyl iminodiacetate. With para-substituted phenols and electron-poor catechol, only the monosubstituted benzyliminodiacetic ester is selectively formed in good yield and no disubstituted product is detected. In contrast, electron rich catechols gave mono- or disubstituted derivatives depending on the stoichiometry of ethyliminodiacetate. Furthermore, the reaction is highly regioselective with catechols, since no para derivatives are formed. In addition, we describe a mild acidic hydrolysis of the ester functions, which avoids the degradation of the benzylamine moiety by the quinone methide pathway. So, pure o-hydroxybenzyliminodiacetic acid ligands are obtained in overall good yields.

Full text of DOI:10.1081/SCC-200034816

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Solvent‐ and Catalyst‐Free
Selective Mannich
Reaction on Catechols
and Para Substituted
Phenols: A Convenient
Route to Catechol‐ and
Phenol‐Iminodiacetic Acid
Ligands
Amaury du Moulinet d'Hardemare a , Olivier
Jarjayes a & Florent Mortini a
a Laboratoire d'Etudes Dynamiques et Structurales
de la Sélectivité (LEDSS), Institut de Chimie
Moléculaire de Grenoble,Université J.
Fourier‐Grenoble I, 301 rue de la Chimie, BP 53X,
38041, Grenoble Cedex 9, France
Version of record first published: 12 Jan 2011.
To cite this article: Amaury du Moulinet d'Hardemare , Olivier Jarjayes &
Florent Mortini (2004): Solvent‐ and Catalyst‐Free Selective Mannich Reaction
on Catechols and Para Substituted Phenols: A Convenient Route to Catechol‐ and
Phenol‐Iminodiacetic Acid Ligands, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 34:21, 3975-3988
To link to this article: http://dx.doi.org/10.1081/SCC-200034816

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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 21, pp. 3975–3988, 2004
Solvent- and Catalyst-Free Selective
Mannich Reaction on Catechols
and Para Substituted Phenols:
A Convenient Route to Catechol-
and Phenol-Iminodiacetic Acid Ligands
*
Amaury du Moulinet d’Hardemare, Olivier Jarjayes,
and Florent Mortini
´ ´
Laboratoire d’Etudes Dynamiques et Structurales de la Selectivite,
´ ´
Institut de Chimie Moleculaire de Grenoble, Universite J.
Fourier-Grenoble I, France
ABSTRACT
We have developed a convenient solvent- and catalyst-free selective
Mannich reaction of a variety of para-substituted phenols or catechols
with paraformaldehyde and ethyl iminodiacetate. With para-substituted
*
Correspondence: Amaury du Moulinet d’Hardemare, Laboratoire d’Etudes Dynami-
´
´
´
ques et Structurales de la Selectivite (LEDSS), Universite J. Fourier, 301 rue de la
Chimie, BP 53X, 38041 Grenoble Cedex 9, France; E-mail: amaury.d-hardemare@
ujf-grenoble.fr.
3975
DOI: 10.1081/SCC-200034816
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

3976
du Moulinet d’Hardemare, Jarjayes, and Mortini
phenols and electron-poor catechol, only the monosubstituted benzyl-
iminodiacetic ester is selectively formed in good yield and no disubsti-
tuted product is detected. In contrast, electron rich catechols gave
mono- or disubstituted derivatives depending on the stoichiometry of
ethyliminodiacetate. Furthermore, the reaction is highly regioselective
with catechols, since no para derivatives are formed. In addition, we
describe a mild acidic hydrolysis of the ester functions, which avoids
the degradation of the benzylamine moiety by the quinone methide
pathway. So, pure o-hydroxybenzyliminodiacetic acid ligands are
obtained in overall good yields.
Key Words: Iminodiacetic ligands; Selective Mannich reaction; Solvent
and catalyst free; Para-substituted phenols; Catechols.
INTRODUCTION
Catechol and phenol complexes are of great importance in bioinorganic
and biomedicinal chemistry. For instance, catechol ligands have found appli-
cations as natural and artificial siderophores devoted to the supplementation
of iron (III).[1–3] In another connection, a variety of compounds containing
both the iminodiacetic and the phenol moieties have been studied by
Maddalena et al.[4] and Awaluddin et al.[5] as potential radiopharmaceutical
complexes of 99mTc. We are curently interested in the development of new
radiopharmaceuticals based on 67Ga nuclide with nuclear characteristics
complementary to 99mTc.[6,7] So we decided to study the gallium complexes
of a variety of catechols and phenols derivatized with an iminodiacetic
group. Curiously, no details regarding the synthesis of most of the desired
o-hydroxy-benzyliminodiacetic ester precursors were found in the literature
survey. To achieve the preparation of those compounds, the Mannich reaction
seems to be very attractive because no special equipment is required and only
commercially available starting compounds are needed. As a general case,
this aminomethylation reaction of aromatic compounds is performed in
aqueous alcoholic solvents,[8–10] in benzene,[11] in toluene, or in a mixture
of toluene-ethanol.[12] Mojtahedi et al. have already reported a solvent-free
Mannich reaction on electron rich aromatic compounds, but it involves
both acid (silica gel) and ultrasound activation.[13,14] The procedure described
here appears to be superior to others because it is environmently friendly
(solvent-free and catalyst-free), no special apparatus e.g., microwave oven
is required, and it is equally efficient on electron-poor and electron-rich
phenolic compounds.

Selective Mannich Reaction on Catechols and Para Substituted Phenols
RESULTS AND DISCUSSION
3977
a) Mannich Reaction on Phenols and Catechols
To find optimum conditions for Mannich aminomethylation, cresol 1 was
chosen as a standard substrate. It was reacted in water with formaldehyde,
iminodiacetic acid in strongly basic (aqueous NaOH) condition following
the original method depicted by Schwarzenbach et al.[15] But, by this way it
is impossible to obtain the desired monosubstituted product 2a without the
disubstituted one 2b Eq. (1).
Moreover, the separation of those products (the resulting sodium salts 2a
and 2b, or their hydrochloric salts obtained after acidification), turned out to
be a difficult task. So, to avoid the tedious purification of such ionic com-
pounds and therefore to allow a more accurate column chromatographic pro-
cedure in the separation step, the ethyl ester of iminodiacetic acid was
employed. In counterpart to its hydrophobic and base sensitive nature, the
ester functions imposes a nonaqueous solvent and the absence of strong
base (like NaOH or KOH) during the reaction. The Mannich reaction of
cresol 1 was then attempted in toluene with paraformaldehyde (in excess)
as an anhydrous source of formaldehyde. If toluene proved to be a good
solvent in some Mannich reactions performed at room temperature, in our
case the reaction was very slow. It became only effective at reflux temperature
(1108C) in 48 hours. Worthy of note, the sole product formed during this reac-
tion is the mono ortho-substituted compound 3a Eq. (2). In contrast to the
Schwarzenbach conditions (aqueous NaOH),[15] the ortho-ortho0 disubstituted
compound 3b is not detected, even if a large excess of ethyl iminodiacetate
and paraformaldehyde or prolonged reaction time are used.
In order to simplify this reaction, a solvent-free reaction was attempted
with three representative electron-rich or electron-deficient phenols Eq. (3)
and the results compared to those obtained in toluene.
Equation 1. Aminomethylation of cresol with iminodiacetic acid in basic condition.

3978
du Moulinet d’Hardemare, Jarjayes, and Mortini
Equation 2. Aminomethylation of cresol with ethyl iminodiacetate in toluene.
It is noteworthy that the supression of the solvent did not change the
selectivity of the reaction: only the monosubstituted compounds are again
isolated; no disubstituted compound is detected (even with a large excess of
iminodiacetate ester and paraformaldehyde). The solvent-free reaction proved
to be superior because it ensures a more rapid reaction than in toluene (16
hours against 24 hours) and the temperature may be lowered from 1108C to
508C with no detrimental effect on the yield (Table 1). Furthermore, the
decrease of the temperature seems to be beneficial since an increase of the
yield is noticeable, especially in the case of the derivatives 4 and 5.
Then, this procedure was successfully applied to a variety of para-
substituted phenols (Table 2). After purification, the products are also isolated
in good yield. However, it is not possible to establish a correlation between the
yield and the electron-donating or electron-withdrawing effect of the group
fixed at the para position of the phenol.
An extension of the above procedure has also been conducted on catechol
and 3,4-dihydroxybenzaldehyde, which are interesting starting compounds for
the synthesis of potentialy binucleating ligands for complexation experiments.
The results of Mannich reactions conducted without solvent on such catechols
are summarized on Fig. 1.
Equation 3. Aminomethylation of three representative phenols in toluene or without
solvent.

Selective Mannich Reaction on Catechols and Para Substituted Phenols
3979
Table 1. Mannich reaction with or without solvent on representative
phenols.
Isolated yield after
24 hours in toluene
(reflux, 1108C)
Isolated yield after
16 hours without
solvent (508C)
Products
3a R ¼ Me-
4 R ¼ OHC-
5 R ¼ AcNH-
70%
58%
29%
76%
75%
47%
For the catechol, the reaction is highly regioselective: only the ortho
monosubstituted product 10a was formed during the reaction, and no substi-
tution occured at the para position. On the other hand, it was found that con-
trary to the results obtained with the para-substituted phenols, it is possible in
the case of catechol to enforce the double substitution at the ortho and ortho
positions (product 10b, yield 47%) if two equivalents of ethyl iminodiacetate
are involved during the reaction. It appears that the presence of a second
hydroxy group on catechol enhances the reactivity of the aromatic ring.
In the case of 3,4-dihydroxybenzaldehyde, a deactivated catechol, the
aminoalkylation is limited to the monosubstitution step (yield of 11a, 60%);
even though two equivalents of ethyl iminodiacetate are used or prolonged
reaction time (48 hours), the disubstituted product 11b is not observed.
Here again the reaction is highly regioselective since only the meta (with
respect to the aldehyde) regioisomer 11a is isolated as a sole new reaction
product. This structural assignment of 11a was unequivocaly based on the
observation of two distinct aromatic protons showing a typical 4JH-H coupling
1
value (4JH-H ¼ 1.8 Hz) in H NMR analysis.
b) Hydrolysis of the Ester Function
The synthezised compounds possess latent carboxylic acid groups that
could be simply regenerated from ester by saponification or acid hydrolysis.
Table 2. Mannich reaction without solvent with ethyl iminodiacetate and p-phenols
at 508C.
Product
3a
4
5
6
7
8
9
R¼
Me
76%
CHO
75%
AcNH
47%
CH2CO2Et
74%
NO2
74%
F
73%
MeO
72%
Yield

3980
du Moulinet d’Hardemare, Jarjayes, and Mortini
Figure 1. Mannich reaction on catechol and 3,4-dihydroxybenzaldehyde without
solvent.
The former method is not advantageous since sodium or potassium salts,
which are hygroscopics and difficult to purify, are obtained. Finally, we
chose to remove the ester function by hydrolysis with aqueous hydrochloric
acid. Preliminary results show that the treatment of the esters with hydro-
chloric acid at high or moderate concentration [(HCl) ¼ 10 M to 5 M)] and
at the refluxing temperature is not satisfactory because the deamination of
the product was observed. Indeed, a substantial amount of iminodiacetic
acid is isolated after refluxing the compounds during the time necessary to
obtain a complete removing of the esters. This reactivity is very likely due
to a retro-Michael reaction involving a quinone methyde intermediate
Eq. (4) as reported by Tramontini and Angliolini.[16]
Equation 4. Retro-Michael activated by acidic catalysis.

Selective Mannich Reaction on Catechols and Para Substituted Phenols
3981
To supress this side reaction, a simple decrease of the temperature from
reflux to 508C is sufficient to ensure a quantitative, clean, and smooth hydroly-
sis of the esters function to give the targets compounds in pure form.
In conclusion, by a simple solvent-free and catalyst-free Mannich reac-
tion with ethyl iminodiacetate and phenols or catechols, we achieved the
selective synthesis of pure esters precursors of chelating compounds in
good yields. This result points out the interest of performing Mannich reac-
tions without solvent. The subsequent hydrolysis of the esters was optimized
to lead in a quantitative yield to the desired ligands. The gallium complexes of
those compounds are under study.
EXPERIMENTAL
Reagents are commercially available from Aldrich and Acros companies
and were used without further purification. Solvents were dried and distilled
before utilization. Melting points were determined on a Bu¨chi-Totoli capillary
aparatus and were uncorrected. The NMR spectra were obtained with a Bruker
Avance 300 (300 MHz for 1H, 282.4 MHz for 19F, and 75.5 MHz for 13C) or a
1
Bruker AM 200 (200 MHz for H and 50 MHz for 13C). The chemical shifts
1
are reported in ppm downfield from internal Me4Si for H and 13C (CDCl3
1
as solvent), from internal sodium trimethylsilylpropansulfonate for H and
13C (D2O as solvent) and from external CFCl3 for 19F. MS was recorded on
Nermag-R10 spectometer. IR spectra were recorded (Nicolet Impact 400
apparatus) as KBr pellets for solid and as films between KBr discs for
liquids. TLC was carried out on precoated Merck silica gel aluminium
plates 60F254. Column chromatography was performed using silica gel 60
(230–240 mesh). The elemental analysis was carried out at the Service
Central d’Analyse du CNRS (Vernaison, France).
A) Mannich Reactions on Phenols and Catechols
General Procedure I for the Mannich Reaction in Toluene
In a 50-mL flask, p-phenols or catechols (1 mmol), and ethyl iminodiace-
tate (1 mmol), and paraformalehyde (1.1 mmol) were refluxed in 10 mL of
toluene under positive pressure of argon. Two additions of paraformalehyde
were introduced at 12 and 36 hours in order to compensate the sublimation
of paraformalehyde. After 48 hours, the toluene was evaporated and the
oily residue was purified by column chromatography over silicagel to give
the pure product.

3982
du Moulinet d’Hardemare, Jarjayes, and Mortini
General Procedure II for the Solvent-Free Mannich Reaction with
Para-Substituted Phenols or Catechols
A typical procedure is as follows: para-substituted phenol or catechol
(1 mmol), ethyl iminodiacetate (1 mmol or 2 mmol for disubstitution), and
paraformaldehyde (1.1 mmol or 2.2 mmol for disubstitution) were stirred at
508C for 16 hours under positive pressure of argon. The oily residue was
then purified by column chromatography over silica gel with the appropriate
eluent to give after evaporation of the solvents a microcrystalline solid (except
for compounds 8, 10b, and 11a, which are obtained as oils).
-[Ethoxycarbonylmethyl-(2-hydroxy-5-methyl-benzyl)-amino]-acetic
acid ethyl ester 3a: Eluent CH2Cl2/ethyl acetate 95/5 to 90/10. Procedure I
1
yield: 70%. Procedure II yield: 76%. Mp 65–668C. H NMR (200 MHz,
3
CDCl3): d 1.24–1.31 (t, J ¼ 7.2 Hz, 6H), 2.23 (s, 3H), 3.52 (s, 4H), 3.94
3
4
(s, 2H), 4.15–4.25 (q, J ¼ 7.2 Hz, 4H), 6.76 (d, J ¼ 1.7 Hz, 1H), 6.76–
3
3
4
6.80 (d, J ¼ 8.2 Hz, 1H), 6.97–7.02 (dd, J ¼ 8.2 Hz, J ¼ 1.7 Hz, 1H), 9.5
(s, O-H, 1H). 13C NMR (50.3 MHz, CDCl3): d 14.1, 20.3, 53.8, 56.2, 61.0,
116.3, 120.9, 128.2, 129.8, 130.0, 155.1, 170.7. IR (neat, KBr): (O-H) 3265,
(C-H) 2979, (C55O) 1746, (C-O) 1192 cm21. MS (CI, NH3 þ isobutane)
m/z: 310 (M þ Hþ, 100%), 190 [HN(CH2CO2Et)2 þ Hþ]. Anal. calcd. for
C16H23NO5: C, 62.12; H, 7.49; N, 4.53; O, 25.86. Found: C, 62.42; H, 7.47;
N, 4.64; O, 25.74.
-[Ethoxycarbonylmethyl-(5-formyl-2-hydroxy-benzyl)-amino]-acetic
acid ethyl ester 4: Eluent CH2Cl2/ethyl acetate 9/1. Procedure I yield: 58%.
Procedure II yield: 75%. Mp: 36–378C. 1H NMR (200 MHz, CDCl3): d 1.25–
1.32 (t, 3J ¼ 6.9 Hz, 6H), 3.53 (s, 4H), 4.05 (s, 2H), 4.17–4.28 (q, 3J ¼ 6.9 Hz,
3
4
4H), 6.98–7.00 (d, J ¼ 8.6 Hz, 1H), 7.57 (d, J ¼ 1.7 Hz, 1H), 7.72–7.77
3
4
(dd, J ¼ 8.6 Hz, J ¼ 1.7 Hz, 1H), 9.82 (s, 1H), 10.35 (s, OHphenol, 1H).
13C NMR (50.3 MHz, CDCl3): d 14.1, 53.9, 55.7, 61.3, 117.2, 121.9, 128.8,
131.2, 132.7, 163.5, 170.7, 190.6. IR (neat, KBr): (O-H) 3249, (C-H) 2987,
(C55O) 1755, (C55O) 1682, (C-O) 1191 cm21. MS (CI, NH3 þ isobutane)
m/z: 324 (M þ Hþ, 100%), 190 [HN(CH2CO2Et)2 þ Hþ]. Anal. calcd. for
C16H21NO6: C, 59.43; H, 6.55; N, 4.33; O, 29.69. Found: C, 59.21; H, 6.51;
N, 4.30; O, 29.54.
-[(5-Acetylamino-2-hydroxy-benzyl)-ethoxycarbonylmethyl-amino]-
acetic acid ethyl ester 5: Eluent CH2Cl2/CH3CN 100/0 to 70/30. Yield pro-
cedure I: 29%. Yield procedure II: 47%. Mp: 91–928C. 1H NMR (200 MHz,
3
CDCl3): d 1.24–1.31 (t, J ¼ 7.2 Hz, 6H), 2.13 (s, 3H), 3.52 (s, 4H), 3.95
3
3
(s, 2H), 4.15–4.25 (q, J ¼ 7.2 Hz, 4H), 6.80–6.85 (d, J ¼ 8.6 Hz, 1H),
3
4
4
7.13–7.19 (dd, J ¼ 8.6 Hz, J ¼ 2.7 Hz, 1H), 7.26–7.27 (d, J ¼ 2.7 Hz,
1H), 9.40 (s, OHphenol, 1H). NMR (50.3 MHz, CDCl3): d 14.2, 24.3, 53.9, 56.3,
61.1, 116.7, 121.4, 121.8, 122.1, 129.4, 154.3, 168.0, 170.6. IR (neat, KBr):

Selective Mannich Reaction on Catechols and Para Substituted Phenols
3983
(O-H þ N-H) 3281, (C-H) 3102, (C-H) 2987, (C55O) 1739, (C55O) 1657, (C-O)
1191 cm21. MS (CI, NH3 þ isobutane) m/z: 353 (M þ Hþ, 100%), 190
[HN(CH2CO2Et)2 þ Hþ]. Anal. calcd. for C17H24N2O6: C, 57.94; H, 6.86; N,
7.95; O, 27.24. Found: C, 57.26; H, 6.91; N, 7.95; O, 27.61.
-f3-[(Bis-ethoxycarbonylmethyl-amino)-methyl]-4-hydroxy-phenylg-
acetic acid ethyl ester 6: Eluent CH2Cl2/ethyl acetate 8/2. Procedure II
yield: 77%. Mp: 48–498C. 1H NMR (200 MHz, CDCl3): d 1.24–1.32
3
3
(t, J ¼ 7.2 Hz, 6H), 1.58–1.61 (t, J ¼ 6.2 Hz, 1H, OH), 3.53 (s, 4H), 3.98
3
3
(s, 2H), 4.15–4.26 (q, J ¼ 7.2 Hz, 4H), 4.55–4.58 (d, J ¼ 6.2 Hz, 2H),
3
4
6.85–6.89 (d, J ¼ 8.2 Hz, 1H), 6.99–7.00 (d, J ¼ 2.1 Hz, 1H), 7.17–7.21
(dd, 3J ¼ 8.2 Hz, 4J ¼ 2.1 Hz, 1H), 9.44 (s, OHphenol, 1H). 13C NMR
(50.3 MHz, CDCl3): d 14.1, 53.9, 56.2, 61.1, 65.1, 116.7, 121.3, 128.7,
128.8, 131.7, 157.2, 170.7. IR (neat, KBr): (O-H) 3355, (C-H) 2987, (C55O)
1739, (C-O) 1192 cm21. MS (CI, NH3 þ isobutane) m/z: 326 (M þ Hþ,
100%), 190 [HN(CH2CO2Et)2 þ Hþ]. Anal.calcd. for C16H23NO6: C, 59.06;
H ¼ 7.13; N ¼ 4.31; O ¼ 29.50. Found: C, 58.97; H, 7.23; N, 4.53; O, 29.53.
-[Ethoxycarbonylmethyl-(2-hydroxy-5-nitro-benzyl)-amino]-acetic acid
1
ethyl ester 7: Eluent CH2Cl2. Procedure II yield 74%. Mp: 758C. H NMR
(300 MHz, CDCl3): d 1.24–1.29 (t, 3J ¼ 7.0 Hz, 6H), 3.51 (s, 4H), 4.02
3
3
(s, 2H), 4.16–4.24 (q, J ¼ 7.0 Hz, 4H), 6.89–6.93 (d, J ¼ 9.0 Hz, 1H),
4
3
4
7.92–7.93 (d, J ¼ 2.7 Hz, 1H), 8.07–8.11 (dd, J ¼ 9.0 Hz, J ¼ 2.7 Hz,
1H), 10.49 (s, OHphenol, 1H). 13C NMR (75.46 MHz, CDCl3): d 14.0, 53.9,
55.4, 61.3, 117.0, 121.6, 125.7, 125.8, 140.1, 163.6, 170.6. IR (neat, KBr):
(O-H) 3200, (C-H) 3040, (C-H) 2980, (C55O) 1715, (N-O) 780 cm21. MS
(CI, NH3 þ isobutane) m/z: 341 (M þ Hþ, 100%), 190 [HN(CH2CO2Et)2 þ
Hþ]. Anal. calcd. for C15H20N2O7: C, 52.94; H ¼ 5.92; N ¼ 8.23;
O ¼ 32.91. Found: C, 53.35; H, 5.89; N, 8.64; O, 32.54%.
-[Ethoxycarbonylmethyl-(5-fluoro-2-hydroxy-benzyl)-amino]-acetic
acid ethyl ester 8: Eluent CH2Cl2/ethyl acetate 95/5. Procedure II yield: 73%
(oil). 1H NMR(300MHz, CDCl3):d 1.25–1.30(t, 3J ¼ 7.2 Hz, 6H), 3.51(s, 4H),
3
3
3.94 (s, 2H), 4.19–4.23 (q, J ¼ 7.2 Hz, 4H), 6.67–6.71 (dd, J ¼ 8.7 Hz,
4J ¼ 2.9 Hz, 1H), 6.78–6.85 (m, 1H), 6.86–6.92 (m, 1H), 9.10 (s, OHphenol
,
1H). 13C NMR (75.46 MHz, CDCl3): d 14.1, 53.8, 55.8, 61.1, 115.4, 115.6,
115.8, 115.9, 117.3 et 117.4, 153.43–153.41 (C-F), 157.5, 170.7. 19F RMN
(282.39 MHz, CDCl3): d 2 126.32. IR (neat, KBr): (O-H) 3346, (C-H) 2987,
(C55O) 1739, (C-O) 1200, (C-F) 1020cm21. MS (CI, NH3 þ isobutane) m/z:
314 (M þ Hþ, 100%), 190 [HN(CH2CO2Et)2 þ Hþ]. Anal. calcd. for
C15H20NO5F: C, 57.50; H, 6.43; N, 4.47. Found: C, 57.58; H, 6.45; N, 4.42.
-[Ethoxycarbonylmethyl-(2-hydroxy-5-methoxy-benzyl)-amino]-acetic
acid ethyl ester 9: Eluent CH2Cl2/ethyl acetate 8/2. Procedure II yield:
1
3
72%. Mp: 768C. H NMR (300 MHz, CDCl3): d 1.25–1.30 (t, J ¼ 7.2 Hz,
3
6H), 3.52 (s, 4H), 3.72 (s, 3H), 3.94 (s, 2H), 4.16–4.23 (q, J ¼ 7.2 Hz,

3984
du Moulinet d’Hardemare, Jarjayes, and Mortini
4
4H), 6.54–6.55 (d, J ¼ 2.7 Hz, 1H), 6.73–6.83 (m, 2H), 8.93 (s, OHphenol
,
1H). 13C NMR (75.46 MHz, CDCl3): d 14.5, 53.8, 55.7, 56.3, 61.0, 114.3,
115.3, 117.0, 121.9, 151.3, 152.5, 170.7. MS (CI, NH3 þ isobutane) m/z:
326 (M þ Hþ, 100%), 190 [HN(CH2CO2Et)2 þ Hþ]. Anal. calcd. for
C16H23NO6: C, 59.06; H, 7.13; N, 4.31. Found: C, 58.8; H, 7.16; N, 4.20.
-[(2,3-Dihydroxy-benzyl)-ethoxycarbonylmethyl-amino]-acetic acid
ethyl ester 10a: Eluent CH2Cl2/ethyl acetate 95/5 to 90/10. Procedure I
1
yield: 54%. Procedure II yield: 70%. Mp: 39–408C. H NMR (300 MHz,
3
CDCl3): d 1.26–1.30 (t, J ¼ 7.2 Hz, 6H), 3.52 (s, 4H), 3.95 (s, 2H), 4.17–
4.25 (q, 3J ¼ 7.2 Hz, 4H), 5.67 (s, Hcatechol, 1H), 6.50–6.53 (dd,
3J ¼ 7.6 Hz, 4J ¼ 1.6 Hz, 1H), 6.67–6.72 (m, 3J ¼ 7.6 Hz, 4J ¼ 7.6 Hz,
3
4
1H), 6.86–6.89 (dd, J ¼ 7.6 Hz, J ¼ 1.6 Hz, 1H), 9.68 (s, OHcatechol, 1H).
13C NMR (75.46 MHz, CDCl3): d 14.1, 54.0, 56.0, 61.2, 114.5, 119.6, 120.5,
121.4, 143.9, 145.1, 171.0. IR (neat, KBr): (O-H) 3500–3200, (C-H) 3061,
(C-H) 2979, (C55O) 1730, (C-O) 1200 cm21. MS (CI, NH3 þ isobutane)
m/z: 312 (M þ Hþ, 100%), 190 [HN(CH2CO2Et)2 þ Hþ]. Anal. calcd. for
C15H21NO6: C, 57.87; H, 6.80; N, 4.50. Found: C, 57.94; H, 6.88; N ¼ 4.62.
-(f4-[(Bis-ethoxycarbonylmethyl-amino)-methyl]-2,3-dihydroxy-benzylg-
ethoxycarbonylmethyl-amino)-acetic acid ethyl ester 10b: Eluent
CH2Cl2/ethyl acetate 95/5 to 90/10. Procedure I yield: 44%. Procedure II
1
3
yield: 47% (oil). H NMR (200 MHz, CDCl3): d 1.20–1.31 (t, J ¼ 7.2 Hz,
12H), 3.54 (s, 8H), 3.96 (s, H), 4.14–4.25 (q, 3J ¼ 7.2 Hz, 8H), 6.48 (s, 2H),
8.85 (s, OHcatechol, 2H). 13C NMR (50.3 MHz, CDCl3): d 14.1, 53.9, 55.5, 60.9,
119.8, 121.9, 145.2, 170.7. IR (neat, KBr): (O-H) 3363, (C-H) 2979, (C55O)
1730, (C-O) 1200 cm21. MS (CI, NH3 þ isobutane) m/z: 513 (M þ Hþ), 324
[M þ Hþ-HN(CH2CO2Et)2], 190 [HN(CH2CO2Et)2 þ Hþ]. Anal. calcd. for
C15H21NO6: C, 56.24; H, 7.08; N ¼ 5.47. Found: C, 55.86; H, 7.09; N, 5.52.
-[Ethoxycarbonylmethyl-(5-Formyl-2,3-dihydroxy-benzyl)-amino]-
acetic acid ethyl ester 11a: Eluent CH2Cl2/ethyl acetate 95/5 to 90/10. Pro-
1
cedure II yield 59% (oil). H NMR (200 MHz, CDCl3): d 9.78 (s, 1H), 7.40
4
4
3
(d, J ¼ 1.8 Hz, 1H), 7.15 (d, J ¼ 1.8 Hz, 1H), 4.23 (q, J ¼ 6.8 Hz, 4H),
4.03 (s, 2H), 3.53 (s, 4H), 1.29 (t, 3J ¼ 7.18 Hz, 6H). 13C NMR
(75.46 MHz, CDCl3): d 14.1, 53.9, 55.6, 61.4, 115.4, 121.5, 123.5, 129.0,
145.5, 150.0, 170.9, 190.8. MS (CI, NH3 þ isobutane) m/z: 340 (M þ Hþ,
100%), 190 [HN(CH2CO2Et)2 þ Hþ]. Anal. calcd. for C16H21O7N: C,
56.63; H, 6.19; N, 4.13; O, 33.04. Found: C, 56.64; H, 6.17; N, 4.18; O, 32.63.
B) Hydrolysis of the Ester Functions
General procedure: the appropriate ester (1 mmol) was dissolved in 10 M
HCl (50 mL). The mixture was heated overnight at 508C. After cooling, the

Selective Mannich Reaction on Catechols and Para Substituted Phenols
3985
water was evaporated under reduced pressure to give the pure acid, which was
isolated in quantitative yield as the hydrochloric salt (hygroscopic).
-[Carboxymethyl-(2-hydroxy-5-methyl-benzyl)-amino]-acetic acid:
1
from hydrolysis of 3a. H NMR (200 MHz, D2O, pD ¼ 1.6): d 2.08 (s, 3H),
3.94 (s, 4H), 4.36 (s, 2H), 6.70–6.72 (d, 3J ¼ 8.2 Hz, 1H), 7.00
(d, 4J ¼ 1.8 Hz, 1H), 7.04–7.07 (dd, 3J ¼ 8.2 Hz, 4J ¼ 1.8 Hz, 1H). 13C
NMR (50.31 MHz, D2O, pD ¼ 1.6): d 19.7, 54.7, 55.4, 114.9, 116.2, 131.0,
133, 133.7, 153.7, 169.0. IR (KBr disc): (O-H) 3281, (C-Har) 3077, (C-Har)
3012, (C-H) 2963, (C55O) 1722 cm21. MS (FABþ, glycerol matrix) m/z:
254 (M þ Hþ, 100%).
Anal. calcd. for C12H15NO5, HCl, 0.5 H2O: C, 48.24; H, 5.69; N, 4.69.
Found: C, 48.6; H, 5.89; N ¼ 4.82.
-[Carboxymethyl-(5-formyl-2-hydroxy-benzyl)-amino]-acetic acid:
1
from hydrolysis of 4. H NMR (200 MHz, D2O, pD ¼ 11.0): d 3.15 (s, 4H),
3
3
3.61 (s, 2H), 6.60–6.64 (d, J ¼ 8.6 Hz, 1H), 7.63–7.68 (dd, J ¼ 8.6 Hz,
4
4J ¼ 2.3 Hz, 1H), 7.79–7.80 (d, J ¼ 1.7 Hz, 1H), 9.39 (s, 1H). 13C NMR
(75.46 MHz, D2O, pD ¼ 11.0): d 56.2, 56.7, 123.1, 124.3, 130.4, 135, 138,
182.6, 195.8. IR (KBr disc): (O-H) 3306, (C-Har) 3020, (C-H) 2955, (C55O)
1690, (C55O) 1608 cm21. MS (CI, NH3 þ isobutane) m/z: 268 (M þ Hþ).
Anal. Calcd. for C12H13NO6, HCl, 1 H2O: C, 44.79; H, 4.97; N, 4.35.
Found: C, 44.80; H, 4.82; N, 4.3.
-[(5-Amino-2-hydroxy-benzyl)-carboxymethyl-amino]-acetic acid:
1
from hydrolysis of 5. H NMR (300 MHz, D2O, pD ¼ 1.5): d 4.15 (s, 4H),
4.64 (s, 2H), 7.09–7.13 (dd, 3J ¼ 8.3 Hz, 4J ¼ 1 Hz, 1H), 7.40–7.44
3
4
(d, J ¼ 8.3 Hz, 1H), 7.44 (d, J ¼ 1 Hz, 1H). 13C NMR (50.3 MHz, D2O,
pD ¼ 1.5): d 54.8, 55.2, 116.9, 117.6, 122.4, 127.5, 127.9, 156.9, 169.1. MS
(IC, NH3 þ isobutane) m/z: 255 (M þ Hþ, 100%). IR (KBr disc): (O-
H þ N-H) 3400–3200, (C-Har) 3020, (C-H) 2955, (C55O) 1755 cm21. Anal.
Calcd. for C11H14N2O5, 2HCl, 1.5 H2O: C,37.30; H, 5.41; N, 7.91. Found:
C, 37.45; H, 5.27; N ¼ 7.83.
-f3-[(Bis-carboxymethyl-amino)-methyl] 2 4-hydroxy-phenylg-acetic
1
acid: from hydrolysis of 6. H NMR (300 MHz, D2O, pD ¼ 1.4): d 3.70
3
(s, 2H), 4.18 (s, 4H), 4.60 (s, 2H), 6.97–7.00 (d, J ¼ 8.3 Hz, 1H), 7.28
(d, 2J ¼ 2.2 Hz, 1H), 7.28–7.34 (dd, 3J ¼ 8.3 Hz, 2J ¼ 2.2 Hz, 1H). 13C
NMR (50.3 MHz, D2O, pD ¼ 1.4): d 39.6, 54.5, 55.2, 115.3, 116.5, 126.7,
133.8, 134.5, 155.4, 168.8, 177.1. IR (KBr disc): (O-H) 3400–3000,
(C55O) 1738, (C-O) 1200 cm21. MS (FABþ, glycerol matrix) m/z: 298
(M þ Hþ, 100%). Anal. Calcd. for C13H15NO7, HCl, 1.5 H2O: C, 43.27; H,
5.27; N, 3.88. Found: C, 43.36; H, 5.20; N, 3.89.
-[Carboxymethyl-(2-hydroxy-5-nitro-benzyl)-amino]-acetic acid: from
1
hydrolysis of 7. H NMR (300 MHz, D2O, pD ¼ 12): d 3.00 (s, 4H), 3.42
(s, 2H), 6.32–6.35 (d, 3J ¼ 9.2 Hz, 1H), 7.83–7.87 (d, 3J ¼ 9.2 Hz,

3986
du Moulinet d’Hardemare, Jarjayes, and Mortini
2J ¼ 3.1 Hz, 1H), 8.03–8.04 (d, 2J ¼ 3.1 Hz, 1H). 13C NMR (50.3 MHz,
D2O, pD ¼ 12): d 54.7, 59.1, 119.7, 127.5, 127.8, 129.2, 133.1, 180.2. IR
(KBr disc): (O-H) 3400–3000, (CH) 2996, (CO) 1738 cm21. MS (FABþ, gly-
cerol matrix) m/z: 284 (M þ Hþ, 100%), 282 (M-Hþ). Anal. Calcd. for
C11H12N2O7, HCl, 0.5 H2O: C, 39.63; H, 4.32; N, 8.40. Found: C, 39.67;
H, 4.57; N, 8.17.
-[Carboxymethyl-(5-fluoro-2-hydroxy-benzyl)-amino]-acetic acid:
1
from hydrolysis of 8. H NMR (300 MHz, D2O, pD ¼ 11): d 3.18 (s, 4H),
3.60 (s, 2H), 6.54–6.58 (m, 1H), 6.80–6.6.87 (m, 1H), 7.07–7.12 (m, 1H).
d 55.7, 57.7, 115.5–115.8
13C NMR (75.4 MHz, D2O, pD ¼ 11):
(JC-F ¼ 23 Hz), 116.8–117.2 (JC-F ¼ 29 Hz), 117.1 (JC-F ¼ 7.3 Hz), 124.5–
124.6 (JC-F ¼ 7 Hz), 153.3, 154.6–157.7 (JC-F ¼ 234 Hz), 178.9. 19F NMR
(282.39 MHz, D2O): d 132.05. IR (KBr disc): (O-H) 3400–3000, (C55O)
1738 cm21. MS (FABþ, glycerol matrix) m/z: 258 (M þ Hþ). Anal. Calcd.
for C11H12NO5F, HCl, 0.5 H2O: C, 43.63; H, 4.63; N, 4.63. Found: C,
43.88; H, 4.58; N ¼ 4.51.
-[Carboxymethyl-(2-hydroxy-5-methoxy-benzyl)-amino]-acetic acid:
1
from hydrolysis of 9. H NMR (300 MHz, D2O, pD ¼ 12): d 3.15 (s, 4H),
3
3.58 (s, 2H), 3.76 (s, 3H), 6.55–6.58 (d, J ¼ 8.7 Hz, 1H), 6.73–6.77 (dd,
2
2
3J ¼ 8.7 Hz, J ¼ 3.4 Hz, 1H), 6.97–6.98 (d, J ¼ 3.4 Hz, 1H). 13C NMR
(75.4 MHz, D2O, pD ¼ 12): d 54.8, 57.0, 59.0, 115.1, 117.2, 119.1, 127.3,
148.0, 160.3, 180.5. IR (KBr disc): (O-H) 3224, (C-Har) 3061, (CHþ) 2990,
(C55O) 1747 cm21. MS (FAB , glycerol matrix) m/z: 270 (M þ H ), 137
þ
´
([M þ Hþ-HN(CH2CO2H)2], 100%), 134 [HN(CH2CO2H)2 þ Hþ]. Anal.
Calcd. for C12H15NO6, HCl, 1.5 H2O: C, 43.32; H, 5.47; N, 4.21. Found: C,
43.71; H, 5.65; N ¼ 4.35.
-[Carboxymethyl-(2,3-dihydroxy-benzyl)-amino]-acetic acid: from
1
hydrolysis 10a. H NMR (300 MHz, D2O, pD ¼ 1.9): d 33.95 (s, 4H), 4.41
3
2
(s, 2H), 6.67–6.76 (m, 2H), 6.85–6.88 (dd, J ¼ 7.5 Hz, J ¼ 2.2 Hz, 1H).
13C NMR (75.4 MHz, D2O, pD ¼ 1.9): d 54.7, 55.1, 116.2, 118.6, 121.3,
124.6, 144.8, 145.1, 169.0. IR (KBr disc): (O-H) 3265, (C-Har) 3060, (CH)
2950, (C55O) 1746 cm21. MS (FABþ, glycerol matrix) m/z: 256 (M þ Hþ,
100%). Anal. Calcd. for C11H13NO6, HCl: C, 45.29; H, 4.84; N, 4.80.
Found: C, 44.92; H, 5.18; N, 4.71.
-(f4-[(Bis-carboxymethyl-amino)-methyl]-2,3-dihydroxy-benzylg-
carboxymethyl-amino)-acetic acid: from hydrolysis of 10b. 1H NMR
(300 MHz, D2O, pD ¼ 1.9): d 3.87 (s, 8H), 4.41 (s, 4H), 6.85 (s, 2H). 13C
NMR (75.4 MHz, D2O, pD ¼ 1.9): d 55.1, 56.8, 120.5, 123.8, 146.1, 171.6.
IR (KBr disc): (O-H) 3436, (CHar) 3055, (C-H) 2995, (C55O) 1738 cm21
.
MS (FABþ, glycerol matrix) m/z: 401 (M þ Hþ, 100%). Anal. Calcd. for
C16H20N2O10, 2 HCl, 1 H2O: C, 39.12; H, 4.92; N, 5.70. Found: C, 38.96;
H, 4.90; N, 5.60.

Selective Mannich Reaction on Catechols and Para Substituted Phenols
3987
-[Carboxymethyl-(5-formyl-2,3-dihydroxy-benzyl)-amino]-acetic acid:
from hydrolysis of 11a. 1H NMR (300 MHz, D2O, pD ¼ 1.9): d 9.50 (s, 1 H);
4
7.32 (dd, J ¼ 1.8 Hz, 2H); 4.49 (s, 2H); 3.99 (s, 4H). 13C NMR (75.4 MHz,
D2O, pD ¼ 1.9): d 194.5, 168.6, 152.5, 145.4, 129.0, 115.9, 129.58, 117.1,
54.6, 54.2. IR (KBr disc): (OH) 3355, (CHar) 3120, (CH) 2990, (CO)
1746 cm21. MS (FABþ, glycerol matrix) m/z: 284 (M þ Hþ, 100%). Anal.
Calcd. for C12H13NO7, 1HCl: C, 45.08; H, 4.41; N, 4.38. Found: C, 44.71;
H, 4.70; N, 4.29.
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Received in Poland June 20, 2004