P. Bovonsombat et al.
Tetrahedron Letters xxx (xxxx) xxx
Table 2
DMSO optimization for the iodination of methyl 2-aminobenzoate 11.a
Entry
Additive
Amount (mmol)
11 (%)
11a (%)
1
2
3
4
5
6
7
8
DMSO
DMSO
DMSO
DMSO
DMSO
DMSOb
DMSOc
DMSO
DMSO
DMF
None
1.0
2.0
3.0
3.5
3.5
3.5
4.0
5.0
3.5
3.5
54
41
35
31
25
35
23
27
25
44
37
46
59
65
69
75
65
77
73
75
56
63
9
10
11
Formamide
a
Reagents and conditions: iodine (1.5 mmol) was added to a solution of methyl
2-aminobenzoate 11 (1.0 mmol) and DMSO (1–5 mmol) or DMF or formamide
(3.5 mmol each) in MTBE (2 mL). The resulting mixture was stirred at room tem-
perature for 1 h, then diluted with diethyl ether (15 mL) and quenched with 10%
aqueous Na2S2O3 (2 mL). The yield was determined by GC/ MS.
b
In acetonitrile (2 mL).
In diethyl ether (2 mL).
c
Scheme 1. Selected iodination reactions of aniline and its derivatives.
aniline analogues: N-methylaniline (1), N-ethylaniline (2), N,N-
dimethylaniline (3), N,N-diethylaniline (4), o-toluidine (5), and
m-toluidine (6), p-toluidine (7), and aniline (8). Except for com-
pounds 4 and 7, which showed significant enhancement with
DMSO, substrates 1–3, 5, 6 and 8 showed either no enhancement
or only a slight enhancement with DMSO (Table 3, entries 1–16).
In fact, higher yields of 1a, 2a, 6a and 8a were obtained without
DMSO and interestingly, in the case of 2, a 30-minute reaction time
extension increased the yield from 65% to 78% (Table 3, entry 3). A
slightly increased yield was observed in the DMSO-assisted iodina-
tion of 3 and 5 (Table 3, entries 5–6 and 9–10). On the other hand,
notable enhancement was observed with DMSO for the iodination
of 4 and 7, which gave 4a and 7a in 85% and 77% yield, respectively,
compared to 70% and 45% yield, respectively, without DMSO
(Table 3, entries 7–8 and 13–14). DMSO assistance in the iodina-
tion of highly activated aniline systems (1–8) was not consistent.
Nevertheless, the iodination in MTBE without DMSO using 1.5
equivalents of iodine represents a suitable method for obtaining
high yields of the iodinated products.
The effect of DMSO enhancement is significant with aniline ana-
logues containing morpholinyl and piperazinyl rings, as well as
electron-withdrawing substituents. The iodinations of N-
phenylpiperazine (9) and N-phenylmorpholine (10) are both
enhanced by the addition of DMSO, resulting in the yields of 9a
and 10a increasing from 61% to 82% and 63% to 91%, respectively
(Table 3 entries 17–20). The iodination of electron-withdrawing
group containing anilines, such as 2-methyl carboxylate (11), 4-
bromo (12) and 4-cyano (13), 2-cyano (14) and 3-cyanoanilines
(15), were best with DMSO, affording 11a-15a in 71–96% yield
(Table 3, entries 21–30).
A mechanism for the interaction of DMSO and iodine is pro-
posed in Scheme 2. A halogen bond (HB) is envisaged between
the HB-accepting oxygen of DMSO and the sigma hole of iodine
(HB-donor). Such an interaction has been demonstrated in the
study of the reaction mechanism of iodine-catalysed Michael addi-
tion [10], and in the UV–visible spectroscopic study of DMSO and
iodine in carbon tetrachloride [11]. The interaction between the
oxygen of DMSO and iodine is thought to lead to heterolytic cleav-
age of the diiodine bond, resulting in an iodonium ion coordinated
to the oxygen of DMSO (complex I).
In the iodination reactions without DMSO, we postulate that it
is the nitrogen of the aniline analogue that coordinates with iodine
through a halogen bond between the nitrogen lone pair and the
sigma-hole of iodine (complex II, Scheme 3). A halogen bond
between the oxygen lone pair of MTBE and iodine is also possible;
Table 1
Solvent optimization for the iodination of methyl 2-aminobenzoate.a
Entry
Solvent
11 (%)
11a (%)
para-Selectivity (%)
1
2
3
4
5
6
7
8
CH3CH2OH
CH3OH
EtOAc
CH3CN
Formamide
DMF
DMSO
CH2Cl2
CHCl3
46
43
48
40
29
27
24
49
66
46
52
50
54
54
56
52
60
70
68
76
49
33
53
47
49
46
99
99
99
100
98
93
100
97
98
97
9
10
11
12
13
Cyclohexane
(CH3CH2)2O
THF
100
99
100
MTBE
a
Reagents and conditions: iodine (1.5 mmol) was added to a solution of methyl
2-aminobenzoate 11 (1.0 mmol) in solvent (2 mL). The resulting mixture was
stirred at room temperature for 1 h, then diluted with diethyl ether (15 mL) and
quenched with 10% aqueous Na2S2O3 (2 mL). The yield was determined by GC/ MS.
when MTBE was mixed with DMSO, higher yields of the iodinated
aniline derivatives were obtained. Subsequently, a study of differ-
ent DMSO proportions in MTBE was conducted where 3.5 equiva-
lents of DMSO was found to be optimum (Table 2, entry 5). To
further ensure that MTBE was the optimum solvent with DMSO,
the iodination of 11 was conducted in other solvents that also gave
excellent para-selectivity. Iodination in acetonitrile and diethyl
ether gave 11a in 65% and 77% yield, respectively (Table 2, entries
6 and 7). The lower yield in acetonitrile rendered it unsuitable and,
due to our tropical climate, diethyl ether is also unsuitable despite
its slightly higher yield. Based on these findings, the reaction con-
ditions consisting of MTBE as the solvent and 3.5 equivalents of
DMSO were adopted in the ensuing study of other aniline
analogues.
The results of the room temperature iodination of aniline
derivatives are shown in Table 3. The enhancing effect of DMSO
toward iodination was not uniform among the highly activated
2