1212
S. Bijani et al. / Tetrahedron Letters 56 (2015) 1211–1214
(alkyl, –OH, –NH2, –COOH, etc.) aromatics and concluded that
Pd/C is suitable as an aliphatic substituent, while Pt/C is effective
for aromatic deuteration. However, several of these methods lack
in functional group tolerance, need vast amount of catalysts, or
require a classy deuterium atmosphere with special apparatus,
leading to low deuterium efficiency. There are very limited stud-
ies on poly-functional aromatics, much less on a drug. Recently,
Sajiki et al.19 have reported the deuteration of Ibuprofen, which
has an aromatic and aliphatic component with –COOH far away
from aromatics, by sequential use of Pd/C and Pt/C catalysts.
Mesalamine,20 also known as Mesalazine or 5-aminosalicylic
acid (5-ASA) 1a, is the therapeutically active moiety of sulfasala-
zine21 used to treat inflammatory bowel disease, such as ulcerative
colitis and mild-to-moderate Crohn’s disease. Chemically, –OH,
–NH2, and –COOH are attached to the benzene ring, which makes
it a poly-functional aromatic compound.
phenol in recent literature19 hints at the possibility of electrophilic
type substitution in these reactions (Fig. 2).
Such pronounced regioselectivities are nullified, when
N-acetylated Mesalamine 1c is deuterated (Fig. 1). Such mechanis-
tic insights are also substantiated by the fact that electron with-
drawing groups for example –COOH, –NO2, and –NHCOCH3
reduce reactivity, evidenced by lower levels of deuteration or
longer reaction times or the requirement of more catalysts.
Apparently, these mechanistic insights for C–H to C–D transforma-
tions may have a significant impact on the fast emerging field of
C–H activation13 and the weak coordination of Pd.12
With a view to enhancing the efficiency of deuteration, the role
of a mixture of both catalysts was examined. Thus, entries 3–7
(Table 2) describe the varying weight percent of 10% Pd/C and
10% Pt/C, which was heated for 48 h in a sealed tube in an atmo-
sphere of H2 gas. In these experiments, there is gradual increase
of Pt/C, while maintaining an overall weight percent of mixed
catalysts around 25–35% with respect to the substrate. As the
results indicate, entry 7 with 10 weight percent of 10% Pd/C and
25 weight percent of 10% Pt/C, was found to afford optimum
deuterium incorporation and the highest overall yields.
Subsequent optimization studies were focused on the duration
of heating at 145 °C, by maintaining catalyst weight, and a ratio
similar to entry 7. The efficiency of deuteration was examined at
4 h, 8 h, 12 h, 16 h, 20 h, 24 h, and 36 h (Table 2, entries 8–14).
As data indicate, the best results could be obtained in 24 h (Table 2,
entry 13) itself, which was half the time required in entry 7 (48 h).
Thus, excellent deuterium efficiency was achieved with ꢀ99.8%
deuteration of 5-aminosalicylic acid 1a to get deuterated 5-amino-
salicylic acid 1b (Table 2, entry 13).
The relevance of H2 purging and the maintenance of the H2
atmosphere was further confirmed by performing the reaction
without/in absence of hydrogen using the same reaction conditions
(Table 2, entry 15),23 but results indicate that the presence of
hydrogen is essential. Additionally, the role of temperature was
also examined and the optimized reaction conditions of entry 13
were subjected to deuteration at room temperature, under identi-
cal conditions. Once again, a significant lowering in deuteration
efficiencies was observed. The catalyst used in the reaction was
found to be satisfactorily recycled up to three catalytic cycles.
The position of deuterium substitution in the aromatic ring and
degree of deuteration have been determined by 1H NMR measure-
ments. Observed typical coupling patterns and J values in 1H NMR
Results and discussion
Initially, we studied the deuteration of 5-aminosalicylic acid
using Rh/C, Pd/C, and Pt/C separately or mixed them as a catalyst
and Table 1 summarizes a comparison of deuterium incorporation.
Deuteration of Mesalamine 1a was conducted by 25 weight
percent of 10% Rh/C (Table 1, entry 1), 25 weight percent of 10%
Pd/C (Table 1, entry 2), and 25 weight percent of 10% Pt/C at
150 °C for 48 h (Table 1, entry 3) in a sealed tube. All these studies
involved purging and maintenance of the H2 atmosphere. Mixed
catalytic systems were also employed and unexpected variance
in deuteration was observed. A combination of Pt and Rh afforded
average deuterium incorporation, while a combination of Pd and
Rh afforded notable regioselectivity (Table 1, entries 4 and 5).
From the above studies, Pd/C and Pt/C, mixed catalysts were
chosen for further optimization (Table 2). As evidenced previously,
Pt/C led to better deuteration of aromatic C–H than Pd/C, under
identical conditions (Table 2, entries 1 and 2).
Although deuteration was incomplete in both cases (Table 2,
entries 1 and 2), but marked regioselectivity in both studies was
noteworthy (Fig. 1). In both the reactions, the C4 position was least
deuterated, which is para to the carboxylic acid group and meta to
the hydroxyl group (Fig. 1).
Indeed the regioselectivity indicates the presence of an
electrophile type D+ reactive species.22 A careful examination of
regioselectivity reported for aniline, benzoic acid, and 2-amino
Table 1
Comparison of deuteration efficiency of different catalytic systemsa
COOH
COOH
H/D
H2N
OH
Catalysts
OH
C6
H2N
D2O
D/H
C3
, H2 atm
C4
D/H
1a
1b
Entry
Catalysts
Temp
Time
% Deuterationb
(°C)
(h)
10%
10%
10%
C3
C4
C6
Pt/C
Pd/C
Rh/C
(% of D)
(% of D)
(% of D)
(% w/w)
(% w/w)
(% w/w)
1
2
3
4
5
6
—
—
25
25
—
—
25
—
—
25
5
25
—
—
10
10
—
150
150
150
150
150
150
48
48
48
48
48
48
79.0
40.8
78.6
70.0
77.0
94.7
76.0
23.8
58.9
53.0
21.0
92.0
84.0
37.9
80.8
72.0
12.0
90.5
20
a
300 mg (1.96 mmol) of 1a was used and reactions were carried out under a H2 atmosphere using the catalyst in D2O (99.9% D content, 12 mL) in a sealed tube.
Deuterium incorporation was determined by quantitative NMR spectroscopy with tert-butanol as an internal reference.
b