A new, one-step, effective protocol for the iodination of aromatic and heterocyclic compounds via aprotic diazotization of amines

Article abstract of DOI:10.1055/s-2006-958936

We have developed a convenient one-step preparation of aromatic and some heterocyclic iodides by the sequential diazotization-iodination of the aromatic amines with a KI/NaNO₂/p-TsOH system in acetonitrile at room temperature. This method has general character and allows aryl iodides with either donor or acceptor substituents in various positions to be obtained from the corresponding amines in 50-90% yield. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-958936

PAPER
81
A New, One-Step, Effective Protocol for the Iodination of Aromatic and
Heterocyclic Compounds via Aprotic Diazotization of Amines
Aprotic
Diazoti
l
zationa
e
ndIodinat
n
ion of
A
rom
a
a
tic and
H
eterocyc
A
lic
A
mines . Krasnokutskaya,*a Nadya I. Semenischeva,a Victor D. Filimonov,a Paul Knochelb
a
Department of Organic Chemistry, Tomsk Polytechnic University, 634050 Tomsk, Russian Federation
Fax +7(3822)563861; E-mail: e_krasnokutskaya@mail.ru
b
Department Chemie, Ludwig-Maximilians-University, Butenandtstrasse 5-13, 81377 Munich, Germany
Fax +49(89)218077680; E-mail: Paul.Knochel@cup.uni-muenchen.de
Received 23 June 2006; revised 6 July 2006
one stage in acetonitrile solution, in the presence of
p-toluenesulfonic acid. There is no need to maintain a low
temperature for these reactions as the process generally
occurs between 10–25 °C, to furnish the iodoarenes in
Abstract: We have developed a convenient one-step preparation of
aromatic and some heterocyclic iodides by the sequential diazotiza-
tion-iodination of the aromatic amines with a KI/NaNO2/p-TsOH
system in acetonitrile at room temperature. This method has general
character and allows aryl iodides with either donor or acceptor sub- high yields (Scheme 1).
stituents in various positions to be obtained from the corresponding
amines in 50–90% yield.
NaNO2, KI
Ar-NH2
Ar-I
Key words: aromatic iodides, aromatic amines, diazotization, po-
tassium iodide, sodium nitrite
MeCN, p-TsOH, 10–25 °C, 50–87%
1–20
1a–20a
Scheme 1
Aromatic iodides are important building blocks in modern
organic synthesis for carbon–carbon bond formation.1 In
addition, many iodoarenes are biologically active mole-
cules that are used as drugs or diagnostic aids, as contac-
tors and radioactively labeled markers in radio-
immunoassay studies and in nuclear magnetic imaging.2
Under optimal reaction conditions, the amine is added to
p-toluenesulfonic acid in acetonitrile. An aqueous solu-
tion of sodium nitrite and potassium iodide is then added
dropwise to the ammonium salt, causing a vigorous emis-
sion of nitrogen. The mixture is stirred until the gas evo-
lution completely stops. The progress of the reaction can
be followed by TLC analysis and by testing for the pres-
ence of the diazonium salt with 2-naphthol. As a rule, full
conversion of the starting amine takes 30–60 minutes
(Table 1).
One of the first and the most commonly used methods for
preparing aromatic iodides is the substitution of a diazo
group by iodine (often called the Sandmeyer reaction).3
The fundamental advantage of this reaction over other
methods involving a direct electrophilic iodination of aro-
matic compounds, is the selective introduction of iodine
into a specified position of the aromatic ring; direct elec-
trophilic iodination frequently gives mixtures of isomers.
This method has rather a general character and allows the
preparation of aromatic iodides containing either donor or
acceptor groups at various positions relative to the amino
group, in good yields. The method also allows diiodo-
arenes to be obtained from the corresponding diamines.
As by-products, the corresponding hydroxy-containing
derivatives are formed in 3–5% (as indicated by GC-MS
analysis) and are readily separated from the desired aro-
matic iodides by chromatographic separation. Adding the
solution of sodium nitrite and potassium iodide whilst
cooling the reaction mixture to 10–15 °C for the first 10
minutes, however, can minimize the amount of phenol
formed.
The process of diazotization-iodination is usually carried
out with sodium nitrite at low temperatures in two steps:
diazotization of the amine in hydrochloric or sulfuric acid
and a subsequent reaction with iodine and KI, sometimes
in the presence of copper salts.3 As an alternative to these
traditional methods, more expensive methods involving
alkyl nitrites in the presence of diiodomethane or other
sources of iodine have been reported.4 Recently, a one-
step method for introducing iodine into an aromatic sub-
strate by a sequence involving diazotization-iodination of
the corresponding amines with HI/KNO2 in DMSO was
suggested.5
Electron donor and electron acceptor functional groups,
which do not occupy an ortho-position to the amine
group, had relatively little influence on the reaction time
and yields (see entries 1, 3, 6, 7, 14). However, steric ef-
fects of ortho-substituents significantly retarded the reac-
tion rate and decreased the yields of the corresponding
aromatic iodides (entries 2, 4, 9, 10, 11, 15, 16, 17). This
deactivation effect was especially strong with di-ortho-
substituted derivatives to the extant that the reaction with
2,6-dinitroaniline did not occur at all, even after pro-
longed heating for 12 h. 2,6-Diethylaniline (15) gave a
Herein, we describe a convenient, alternative method for
the preparation of aromatic iodides by a diazotization–
iodination sequence of the corresponding aromatic
amines. The sequential diazotization-iodination occurs in
SYNTHESIS 2007, No. 1, pp 0081–0084
x
x
.
x
x
.2
0
0
6
Advanced online publication: 12.12.2006
DOI: 10.1055/s-2006-958936; Art ID: Z13006SS
© Georg Thieme Verlag Stuttgart · New York

82
E. A. Krasnokutskaya et al.
PAPER
Table 1 Iodination of Aromatic Amines with NaNO2/KI/p-TsOH in Acetonitrile, at Room Temperaturea
Entry
ArNH2 (1–20)
Time
(min)
Product (1a–20a)
Yield (%)
mp (°C)
Lit. mp (°C)
1
2
4-NO2C6H4NH2
2-NO2C6H4NH2
4-MeCOC6H4NH2
2-MeCOC6H4NH2
2-NH2C6H4CO2H
4-NH2C6H4NH2
4-IC6H4NH2
30
50
30
60
30
30
30
30
60
120
135
30
30
30
60
60
60
4-NO2C6H4I
84
81
87
85
50
50
78
80
73
50
48
80
78
90
75b
78
83
172–173
52–53
1716
47–497
856
2-NO2C6H4I
3
4-MeCOC6H4I
2-MeCOC6H4I
2-IC6H4CO2H
1,4-I2C6H4
84–85
4
oil
–
5
161–162
130–131
130–131
53–54
1626
6
1296
7
1,4-I2C6H4
–
8
2,4,6-Cl3C6H2NH2
2-IC6H4NH2
2,4,6-Cl3C6H2I
1,2-I2C6H4
548
9
oil
–
10
11
12
13
14
15
16
17
2,4,6-I3C6H2NH2
2,4-(NO2)2C6H3NH2
4-PhC6H4NH2
1,2,4,6-I4C6H2
2,4-(NO2)2C6H3I
4-PhC6H4I
162–164
88.5–89
112–113
203–204
51–52
162–1659
88.510
109–11111
204–20511
526
4-NH2C6H4C6H4-4¢-NH2
4-MeOC6H4NH2
2,6-Et2C6H4NH2
2-I-4-NO2C6H3NH2
4-IC6H4C6H4-4¢-I
4-MeOC6H4I
2,6-Et2C6H4I
1,2-I2-4-NO2C6H3
oil
–
110–111
203–204
109–11012
204–20513
O
NH2
O
I
O
O
I
18
19
20
60
76
80
78
52–53
93.5–95
79–80
52.3–5314
91–9315
79–8116
NH2
N
N
N
N
50
NH2
I
Cl
S
Cl
S
210
I
NH2
N
N
a Molar ratio of reagents Ar-NH2–NaNO2–KI–p-TsOH = 1:2:2.5:3.
b t-BuOH was used as solvent.
mixture of 1,3-diethyl-2-iodobenzene (15a) and N-(2,6- Replacing acetonitrile by tert-butanol under the same re-
diethylphenyl)acetamide (15b) in a 1: 1 ratio.
action conditions did, however, allow the desired 1,3-di-
ethyl-2-iodobenzene (15a) to be obtained with 75% yield
(Table 1, entry 15).
NH2
NHAc
Among the heterocyclic amines studied, the reaction
proved to be suitable for obtaining 3-iodopyridines and
1,3-benzothiazol-2-amine (entries 18–20). However, 2-
amino-5-bromopyridine (21) did not furnish the corre-
sponding iodide. In this case, the reaction gave a complex
mixture of products from which N-(5-bromo-2-py-
ridyl)acetamide (21a) and 5-bromo-2-(4-methylphenyl-
I
NaNO2, KI
+
MeCN, p-TsOH, 20 °C
80%
1:1
15a
15b
15
Scheme 2
Synthesis 2007, No. 1, 81–84 © Thieme Stuttgart · New York

PAPER
Aprotic Diazotization and Iodination of Aromatic and Heterocyclic Amines
83
Yield: 0.72 g (73%); colorless oil.
1H NMR (300 MHz, CDCl3): d = 7.03 (ddd, J = 8.0, 1.5, 0.3 Hz,
sulfonyloxy)pyridine (21b) could be isolated in 30% and
15% yield, respectively. Similar problems were encoun-
tered with 2- and 4-aminopyridine and 2-pyrazinamine 2 H), 7.88 (ddd, J = 8.0, 1.5, 0.3 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 107.9, 128.8, 138.9.
(GC-MS data).
1,3-Diethyl-2-iodobenzene (15) and N-(2,6-Diethylphenyl)ace-
tamide (15b)
The reaction mixture was extracted with EtOAc (3 × 20 mL) and the
combined organic layers were dried (MgSO4) and concentrated un-
der vacuum to yield the crude product. Pentane (30 mL) was added
and the insoluble material was filtered off and recrystallized from
hexane to give 15b.
Br
Br
Br
NaNO2, KI
MeCN, p-TsOH, 20 °C
N
NH2
N
+
NHAc
OTs
15b
N
Yield: 0.24 g (42%); colorless crystals; mp 140–141 °C.
Scheme 3
1H NMR (300 MHz, CDCl3): d = 1.1 (t, J = 7.5 Hz, 6 H, CH2CH3),
2.1 (s, 3 H, COCH3), 2.5 (q, J = 7.5 Hz, 4 H, CH2CH3), 7.0–7.1 (m,
3 H).
13C NMR (75 MHz, CDCl3): d = 14.7, 23.5, 25.2, 127.0, 128.6,
142.0, 142.7, 174.0.
In summary, we have developed a novel method for pre-
paring aromatic iodides. It is simple to perform and suit-
able for a wide range of aromatic and some heterocyclic
amines. We have also studied its scope and limitations and
conclude that this methodology should be of value for the
preparation of functionalized unsaturated iodides.
The remaining hexane solution was purified by flash chromatogra-
phy on silica gel (pentane) to give 15a.
15a
Yield: 0.3 g (38%); pale oil.
1H NMR (300 MHz, CDCl3): d = 1.1 (t, J = 7.5 Hz, 6 H), 2.7 (q,
J = 7.5 Hz, 4 H), 6.96 (m, 3 H).
13C NMR (75 MHz, CDCl3): d = 15.1, 36.0, 107.6, 126.3, 128.5,
147.7.
All starting materials were purchased from commercial sources and
used without further purification. Acetonitrile was used as HPLC-
quality from VWR. t-BuOH was distilled over CaH2. Yields refer to
isolated yields of compounds estimated to be > 95% pure as deter-
mined by 1H NMR and capillary GC.
N-(5-Bromo-2-pyridyl)acetamide (21) and 5-Bromo-2-(4-meth-
ylphenylsulfonyloxy)pyridine (21b)
The reaction mixture was extracted with Et2O (3 × 20 mL) and the
combined organic layers were dried (MgSO4) and concentrated un-
der vacuum to yield an oily product which was purified by flash
chromatography (pentane–Et2O, 1:3) to give 21a and 21b.
Synthesis of Aromatic Iodides (1a–20a); General Procedure
To a solution of p-TsOH·H2O (1.719 g, 9 mmol) in MeCN (12 mL)
was added the aromatic amine (3 mmol). The resulting suspension
of amine salt was cooled to 10–15 °C and to this was added, gradu-
ally, a solution of NaNO2 (0.414 g, 6 mmol) and KI (1.245 g, 7.5
mmol) in H2O (1.8 mL). The reaction mixture was stirred for 10 min
then allowed to come to 20 °C and stirred until the total time indi-
cated in Table 1 had elapsed. To the reaction mixture was then add-
ed H2O (50 mL), NaHCO3 (1 M; until pH = 9–10) and Na2S2O3 (2
M, 6 mL). The precipitated aromatic iodide was filtered or extracted
either with Et2O or EtOAc and purified by flash chromatography
(pentane–Et2O, 1:3 or pentane–CH2Cl2, 5:1).
21a
Yield: 0.2 g (30%); colorless crystals; mp 181–182 °C).
1H NMR (300 MHz, CDCl3): d = 2.1 (s, 3 H, COCH3), 7.7 (dd,
J = 7.8, 2.1 Hz, 1 H), 8.09 (d, J = 7.8 Hz, 1 H), 8.2 (d, J = 2.1 Hz,
1 H).
13C NMR (75 MHz, CDCl3): d = 24.8, 114.6, 115.4, 141.0, 148.5,
2-Iodacetophenone (4a)
150.2, 168.8.
The synthesis and workup was carried out as described in the gen-
eral procedure. The reaction mixture was extracted with Et2O (3 ×
20 mL) and concentrated under vacuum and the resultant yellow oil
was purified by chromatography (pentane–Et2O, 1:3).
21b
Yield: 0.15 g (15%); pale oil.
1H NMR (300 MHz, CDCl3): d = 2.3 (s, 3 H), 7.0–7.3 (m, 3 H), 7.7–
7.8 (m, 3 H), 8.2 (d, J = 2.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 21.7, 117.3, 118.6, 128.5, 129.7,
132.6, 142.6, 145.6, 149.1, 155.6.
Yield: 0.63 g (85%); yellow oil.
1H NMR (300 MHz, CDCl3): d = 2.47 (s, 3 H, COCH3), 7.0–7.3 (m,
3 H), 7.8 (d, J = 7.8 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 29.1, 90.7, 128.0, 131.6, 140.5,
143.5, 200.1.
Acknowledgment
1,2-Diiodobenzene (9a)
Purified by column chromatography (pentane–CH2Cl2, 5:1).
E.A.K. thanks D. A. A. D. for a research grant in 2006 allowing a
stay at the Ludwig-Maximilians-University of Munich.
Synthesis 2007, No. 1, 81–84 © Thieme Stuttgart · New York

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PAPER
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Synthesis 2007, No. 1, 81–84 © Thieme Stuttgart · New York