H5IO6/KI: A new combination reagent for iodination of aromatic amines, and trimethylsilylation of alcohols and phenols through in situ generation of iodine under mild conditions

Article abstract of DOI:10.1002/hlca.200900259

A simple method for the in situ generation of iodine using H ₅IO₆/KI has been developed, and its application in silylation of OH group and iodination of aromatic amines is described.

Full text of DOI:10.1002/hlca.200900259

Helvetica Chimica Acta – Vol. 93 (2010)
587
H5IO6/KI: A New Combination Reagent for Iodination of Aromatic Amines,
and Trimethylsilylation of Alcohols and Phenols through in situ Generation of
Iodine under Mild Conditions
by Mohammad Ali Zolfigol*a), Ardeshir Khazaei*a), Eskandar Kolvari*b), Nadiya Koukabia),
Hamid Soltania), and Maryam Behjuniaa)
a) Faculty of Chemistry, Bu-Ali Sina University, P. O. Box 651783868, Hamedan, Iran
b) Faculty of Science, Department of Chemistry, Semnan University, Semnan, Iran
(e-mail: khazaei_1326@yahoo.com, zolfi@basu.ac.ir, kolvari@semnan.ac.ir)
A simple method for the in situ generation of iodine using H5IO6/KI has been developed, and its
application in silylation of OH group and iodination of aromatic amines is described.
Introduction. – So far, no report has been found in the literature on the in situ
generation of the molecular iodine (I2) by the reaction of iodide salts and orthoperiodic
acid (H5IO6). Previously, I2 has been used only as a reagent, but in recent years, I2-
catalyzed reactions have grown in importance in organic synthesis [1 – 8]. Molecular
iodine (I2) is a versatile catalyst in organic synthesis, but it is highly corrosive, toxic, and
sublimable, making its use somewhat unattractive; also there are some environmental
hazards with respect to its handling. To overcome these disadvantages with I2, an
attempt to introduce I2 in situ in the reaction mixture seems to be practically useful.
During the last years, several new methods for in situ generation of bromine have
been developed [9], but the number of protocols that are available to achieve
molecular iodine in situ in the reaction mixture is limited [10 – 16]. In addition, most of
these protocols suffer from disadvantages such as: complex and strong oxidizing agents,
harsh reaction conditions, and formation of significant amount of waste. Therefore, the
development of quick, inexpensive, widely applicable, and environmentally benign
iodinating agents is still an active area of research.
Orthoperiodic acid (H2IO6) has attracted much interest owing to its potential as
oxidant in organic reactions and transformations [17 – 19]. The use of H5IO6 has been
known for a long time, and it has been widely employed in numerous and different
organic reactions such as iodination [20 – 22] and deprotection [23]. This reagent has
several advantages such as cost-effectiveness, non-toxicity, and the simple and clean
workup of products.
Results and Discussion. – Against the background presented, we have carried out a
detailed investigation aimed at the preparation of in situ generation of the I2 by the
reaction of KI and H5IO6. We found that this system could play a dual role as a reagent
system for iodination of aromatic amines and as a catalyst system in trimethylsilylation
of alcohols and phenols. We assume that our method is general, simple, mild, rapid,
inexpensive, and new.
ꢀ 2010 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Helvetica Chimica Acta – Vol. 93 (2010)
At the beginning of this work, we studied iodination of 4-phenylmorpholine as
model compound with KI and H5IO6 in different solvents (Scheme 1 and Table 1). Our
investigation revealed that, amongst the various solvents, a mixture of CH2Cl2/H2O 1 :1
was the most effective, as a change of color was evident. Also the effective amount of
H5IO6 acid on the reaction was studied, as shown in Table 2; 1.2 mmol of H5IO6 gives a
high yield in a short reaction time.
Scheme 1
Table 1. Comparison of Various Solvents for Iodination of 4-Phenylmorpholine Using H5IO6 and KI
Entry
Solvent
Time [min]
Yield [%]a)
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2/H2O 1 : 1
MeCN
MeCN/H2O 1 : 1
MeCH2OH
THF/H2O 1 : 1
CHCl3
120
25
–
95
30
60
68
80
–
120
120
120
120
120
120
Hexane
–
a) Refers to yields of isolated iodide on reaction of 1.2 mmol of H5IO6 and KI with 4-phenylmorpholine
(1.0 mmol) in 10 ml of solvent or solvent mixture at room temperature.
Table 2. Effect of the Amount of H5IO6 on the Iodination Yield of 4-Phenylmorpholine (1.0 mmol)a)
Entry
H5IO6 [mmol]
Yield [%]b)
1
2
3
4
5
0.4
0.6
0.8
1
30
45
59
82
95
1.2
a) Reaction conditions: KI (1.2 mmol), time: 25 min; solvent: 10 ml of CH2Cl2/H2O 1 : 1; room
temperature. b) Yield of the isolated iodide.
With a better understanding of the reaction variables, a series of aromatic amines
were subjected to iodination with KI and H5IO6 at room temperature in CH2Cl2/H2O
1:1 as a two phase system. In all of the reactions, we observed that mono-iodination
took place regioselectively at the more active and less hindered position (Table 3).
Even though H5IO6/KI is capable of oxidizing alcohol [24], it remains intact during the
iodination of the aromatic nucleus (Entry 4).
Several attempts for mono-iodination of phenols were unsuccessful and led to
mixtures. We have extended our reaction to a series of unactivated aromatic

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589
Table 3. Iodination of Aromatic Amines under Standard Conditions with H5IO6/KI in CH2Cl2/H2O 1 : 1 at
Room Temperaturea)
Entry
1
Substrate
Product
Time [min]
40
Yield [%]b)
90
2
3
70
25
93
95
4
80
88
5
6
60
60
79
98
7
15
95
8
9
No reaction
No reaction
120
120
–
–
10
Sluggish
15
a) See procedure in Exper. Part. b) Yields refer to isolated products which were characterized by
comparison of their spectroscopic and physical data with those of samples synthesized by reported
procedures.
compounds as depicted in Table 3; these compounds remained unchanged even after
2 h (Entries 8 and 9).

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To extend the application of this method, we have employed H5IO6/KI catalytically
for trimethylsilylation of alcohols and phenols. In this context, we have found that a
combination of H5IO6 and a catalytic amount of KI generate in situ I2 as an efficient
catalyst for the trimethylsilylation of alcohols and phenols in the presence of 1,1,1,3,3,3-
hexamethyldisilazane (HMDS; Scheme 2). To find the best system for the in situ
generation of I2, we first studied a number of oxidizing agents in combination of KI for
the trimethylsilylation of alcohols and phenols. As can be seen in Table 4, the best
results were achieved with the H5IO6/KI system.
Scheme 2
Table 4. Comparison between Various Oxidizing Agents/KI Systems for the Trimethlsilylation of Benzyl
Alcohola)
Entry
Oxidant
Time [h]
Yield [%]b)
1
Na2S2O8
2
–
2
K2S2O8
2
–
3
4
Sodium perborate
NH4S2O8
2
2
–
–
5
6
7
8
9
10
11
H5IO6
immediate
8
immediate
2
2
2
2
100
–
100
–
–
–
c
H5IO6
)
–d)
UHPe)
DABCO/DNODPf)
g
PVP/H2O2
Sodium percarbonate
)
–
a) Reaction conditions: Benzyl alcohol (1.0 mmol); oxidant (0.2 mmol); KI (0.2 mmol); 1 ml of
moistened CH2Cl2. b) GC Yield. c) Without KI. d) Reaction conditions: Benzyl alcohol (1.0 mmol); I2
f
(0.1 mmol); 1 ml of moistened CH2Cl2. e) UHP ¼ Urea hydrogen peroxide. ) DABCO/DNODP: 1,4-
Diazabicyclo[2.2.2]octane 1,4-bis(oxide)/bis(hydrogen peroxide). g) Polyvinylpyrrolidone/H2O2 (PVP/
H2O2).
In addition to KI, we also used catalytic amounts of KCl and KBr for silylations. The
results are collected in Table 5. From these results, it is clear that KI is more efficient
than KCl or KBr. Also as a model, we studied the trimethylsilylation of benzyl alcohol
in different solvents (Table 6). Thus, a variety of alcohols and phenols were subjected
to silylation reaction with a combination of H5IO6 and a catalytic amount of KI in the
presence of HMDS. All protection reactions were performed under mild and
homogeneous conditions, at room temperature, and with good-to-high yields. These
reactions were carried out in CH2Cl2 moistened by one drop of H2O (Table 7).
As shown in Table 7, in the cases of primary and secondary alcohols, the reactions
were completed rapidly, and different types of highly hindered tertiary alcohols were
successfully converted to the corresponding trimethylsilyloxy (TMSO) derivatives in

Helvetica Chimica Acta – Vol. 93 (2010)
591
Table 5. Comparison of Various Types of MX for the Trimethylsilylation of Benzyl Alcohola)
Entry
MX
Time [h]
Yield [%]b)
1
2
3
4
KI
immediate
100
–
–
KIc)
KCl
KBr
1
1
1
64
a) Reaction condition: Benzyl alcohol (1.0 mmol); H5IO6 (0.2 mmol); MX (0.2 mmol), 1 ml of
moistened CH2Cl2. b) GC Yield. c) Solvent-free.
Table 6. Comparison of Various Solvents for Trimethylsilylation of Benzyl Alcohol Using I2 Generated in
situ from H5IO6 (0.2 mmol) in the Presence of a Catalytic Amount of KI (0.2 mmol)
Solvent
[ml/drop]
Time [h]
Yield [%]a)
MeCN
2/0
2/1
2/0
5/1
2/1
2/1
2/1
2/0
2
2
2
2
33
75
-
70
100
50
85
–
MeCN/H2Ob)
CH2Cl2
CH2Cl2/H2Ob)
CH2Cl2/H2Ob)
THF/H2Ob)
CHCl3/H2Ob)
Hexane
immediate
2
2
2
a) GC Yields. b) Moistened solvent.
almost quantitative yields at room temperature (Table 7, Entries 18 – 20). Moreover,
no-side products were observed in these reactions.
The data in Table 8 clearly show that different types of phenols were successfully
converted to the corresponding TMSO derivatives in short reaction times and in almost
quantitative yields. We observed that amines and thiols were not silylated under these
conditions even after prolonged reaction times (Table 8, Entries 5 and 6).
For confirming this claim that I2 is the actual catalyst, we conducted trimethylsi-
lylation of PhCH2OH with HMDS in the presence of catalytic amounts of H5IO6
(0.2 mmol) instead of the H5IO6/KI system, no reaction occurred event after 8 h
(Table 4, Entry 6), while PhCH2OH was trimethylsilylated with HMDS in the presence
of H5IO6/KI or I2, in very short reaction times (Table 4, Entries 5 and 7).
Conclusions. – A simple method for the in situ generation of molecular iodine from
nontoxic and commercially available materials has been developed that could be
utilized for a dual role: as a reagent system in iodination of aromatic amines, and as a
catalyst system in trimethylsilylation of alcohols and phenols.
The authors acknowledge Bu-Ali Sina University Research Council (Grant Number 32-1716), Center
of Excellence in Development of Chemical Methods (CEDCM), and National Foundation of Elites
(BMN) for support of this work.

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Table 7. Trimethylsilylation of Alcohols (1 mmol) Using HMDS (1 mmol) Catalyzed with I2 Generated
in situ from H5IO6 (0.2 mmol) in the Presence of a Catalytic Amount of KI (0.2 mmol) in CH2Cl2 and One
Drop of H2O at Room Temperature
Entry Substrate
Product
Time [min] Yield [%]a)
1
2
3
4
5
6
7
8
PhCH2OH
PhCH2OSiMe3
immediate 95
immediate 93
immediate 97
immediate 94
4-MeOꢀC6H4CH2OH
4-ClꢀC6H4CH2OH
2,4-(Cl)2C6H4CH2OH
PhCH2CH2OH
PhCH2CH2CH2OH
PhCH(OH)Ph
4-MeOꢀC6H4CH2OSiMe3
4-ClꢀC6H4CH2OSiMe3
2,4-(Cl)2C6H4CH2OSiMe3
PhCH2CH2OSiMe3
PhCH2CH2CH2OSiMe3
PhCH(OSiMe3)Ph
3
90
immediate 95
92
immediate 90
2
Me(CH2)6CH2OH
Me(CH2)6CH2OSiMe3
9
12
15
91
10
85
11
12
13
immediate 83
60
11
95
98
14
immediate 93
15
16
immediate 94
immediate 94
17
9
91

Helvetica Chimica Acta – Vol. 93 (2010)
593
Table 7 (cont.)
Entry
18
Substrate
Product
Time [min]
Yield [%]a)
93
10
19
20
50
30
85
93
a) Yields refer to isolated products which were characterized by comparison of their spectroscopic and
physical data with those of samples synthesized by reported procedures.
Table 8. Trimethylsilylation of Phenols (1.0 mmol) Using HMDS (1.0 mmol) Catalyzed with I2 Generated
in situ from H5IO6 (0.2 mmol) in the Presence of a Catalytic Amount of KI (0.2 mmol) in CH2Cl2 and One
Drop of H2O at Room Temperature
Entry
1
Substrate
Producta)
Time [min]
immediate
Yield [%]b)
96
2
immediate
97
3
4
5
25
95
immediate
–
92
–
–
no reaction
no reaction
6
–
a
1
) All products were characterized by comparison of their spectral data (IR, H-NMR) with those of
authentic samples. b) Yields of isolated silyl ethers.
Experimental Part
Typical Procedure for Iodination of 4-Phenylmorpholine. To a soln. of 4-phenylmorpholine
(1.0 mmol, 163 mg) in CH2Cl2 (5 ml) were added KI (1.2 mmol, 199 mg) and a soln. of H5IO6 (1.2 mmol,
273 mg) in H2O (5 ml), and the mixture was stirred vigorously for 15 min at r.t. After completion of
reaction, which was indicated by TLC, the mixture was transferred to a separatory funnel, and a 10% aq.

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Helvetica Chimica Acta – Vol. 93 (2010)
Na2S2O3 soln. (25 ml) was added. The aq. fraction was extracted with CH2Cl2 (3 ꢁ 15 ml). The org. layer
was dried (Na2SO4), and the solvent was removed by simple distillation to give a crude product (283 mg;
98%). Further purification was carried out by crystallization from cold hexane to afford the product
(274 mg, 95 %). M.p. 128 – 1308. Satisfactory anal. and spectroscopic properties.
General Procedure for Trimethylsilylation of Alcohols and Phenols. The alcohol or phenol
(1.0 mmol) was added to a mixture of H5IO6 (0.2 mmol) and KI (0.2 mmol) in CH2Cl2 (1 ml), and one
drop of H2O. Then, HMDS (1.0 mmol in 1 ml CH2Cl2) was added dropwise to this mixture within 5 min.
The mixture was stirred vigorously at r.t. for the specified time (Tables 7 and 8). After completion of the
reaction (TLC), the mixture was filtered, and the solids were washed with CH2Cl2 (5 ml). Powdered
Na2S2O3 (12.0 mmol) was added, the mixture was stirred for additional 5 min, and the resulting mixture
was filtered. Finally, H2O (10 ml) was added to destroy the extra amount of HMDS, the org. layer was
separated, and the filtrate was dried (Na2SO4). Evaporation of the solvent under reduced pressure gave
the almost pure product.
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Received July 11, 2009