Understanding and exploitation of neighboring heteroatom effect for the mild N-arylation of heterocycles with diaryliodonium salts under aqueous conditions: A theoretical and experimental mechanistic study

Article abstract of DOI:10.1021/acs.joc.6b00779

The mechanism of arylation of N-heterocycles with unsymmetric diaryliodonium salts is elucidated. The fast and efficient N-arylation reaction is interpreted in terms of the bifunctionality of the substrate: The consecutive actions of properly oriented Lewis base and Br?nsted acid centers in sufficient proximity result in the fast and efficient N-arylation. The mechanistic picture points to a promising synthetic strategy where suitably positioned nucleophilic and acidic centers enable functionalization, and it is tested experimentally.

Full text of DOI:10.1021/acs.joc.6b00779

Subscriber access provided by - Access paid by the | UCSB Libraries
Article
Understanding and Exploitation of Neighboring Heteroatom Effect for
the Mild N-arylation of Heterocycles with Diaryliodonium Salts under
Aqueous Conditions: A Theoretical and Experimental Mechanistic Study
Tamas Bihari, Bence Babinszki, Zsombor Gonda, Szabolcs Kovács, Zoltán Novák, and András Stirling
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00779 • Publication Date (Web): 03 Jun 2016
Downloaded from http://pubs.acs.org on June 9, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 19
The Journal of Organic Chemistry
1
2
3
4
INTRODUCTION
5
6
7
8
In the past two decades hypervalent, λ3-iodane organic compounds have been efficiently
utilized as successful reagents in organic chemistry.1-2 This rising interest in λ3-iodanes is mainly
due to their versatile character, commercial availability, environmental-friendly behavior and
enormous potential in C-C and C-heteroatom couplings. Diaryliodonium salts are particularly
important among the quickly growing number of aryliodonium compounds because they afford
efficient arylation of diverse nucleophiles, in particular heteroatom nucleophiles.2 While arylation
with iodonium salts often requires the presence of transition-metal catalysts,3 recently efficient
metal-free alternative arylation procedures have been developed,4-7 which offer various
advantages, such as less toxicity, higher moisture and air tolerance and lower costs. These
transformations generally require strong bases.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Earlier studies have already pointed out several important aspects of the mechanism of metal-
free arylation by iodonium salts. While in some cases radical mechanism was observed,8 a large
number of arylation reactions follow nonradical pathways.7,9-16 It has been showed both
theoretically10,11,17-20 and experimentally7,11,12,21 that the chemoselectivity of the unsymmetrical
aryliodonium salts are governed by the interplay of the electron deficiencies of the aromatic rings
attached to the iodine center and the steric demand of the ortho ligands on the aryl groups (ortho-
effect22). Quantum chemical calculations have also shown that the selectivity can be predicted by
considering the differences between the activation barriers of the sigmatropic
rearrangements.10,11,18,19
Recently calculations have indicated that the [2,3]-sigmatropic rearrangement is a more
favorable pathway for α-arylation of enolates than the expected [1,2]-rearrangement route,10 and
subsequent experimental work on Ν-arylation of secondary amides also suggested this route.14
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 19
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. Ν-arylation of 3,5-diphenylpyrazole with unsymmetric diaryliodonium triflate.9
Direct arylation of nitrogen-heterocycles is an advantageous way to obtain functionalized
heterocycles at a lower cost. Aryliodonium salts have also been proved to be very efficient for
both C-H arylation and N-functionalization.1c,2a,2c For example N-arylated pyrazoles have been
recently synthetized using diaryliodonium salts (Scheme 1).9 N-arylated pyrazoles are frequently
used molecular motifs for biologically active compounds in medicinal chemistry, therefore
functionalization of pyrazole scaffolds is highly beneficial. A particular advantage of the
methodology is that weak bases are sufficient for optimal performance. The efficiency and the
wide scope of this method offer an ideal opportunity to study the mechanistic aspects of the direct
arylation reactions with iodonium salts. To this end we have followed a computational strategy
where we first probed different possible reaction paths and selected the optimal mechanism by
comparing the free energy profiles. The insights obtained from the results lead us to postulate a
more general mechanistic pattern for the arylation reactions. Then we have tested this mechanism
by predicting the chemoselectivity of the arylation reactions of a diverse set of unsymmetric
iodonium salts taken from our previous work.9 On the basis of the generalized mechanism we can
identify additional scaffolds suitable for N-arylation under mild conditions which further extend
the scope of the methodology.
ACS Paragon Plus Environment

Page 3 of 19
The Journal of Organic Chemistry
1
2
3
4
RESULTS AND DISCUSSION
5
6
7
8
9
We have applied density functional theory and the same methodological framework as in our
earlier study to explore the mechanism of trifluoroethylation of indoles.23 For identifying the
initial resting state we first focused on the possible solvated forms of the iodonium salt. Three
conformations (depending on the equatorial ligand) and the dissociated form have been
considered. We have found that the most stable state is the dissociated form by a few kcal/mol for
several iodonium salts.24 Earlier calculations predicted that the dissociated state is less stable by
1.7 kcal/mol when the solvent is THF.10 This discrepancy points to a role of the solvent in the
mechanism.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 19
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. Possible reaction mechanisms for the arylation with diaryliodonium cation.
We have chosen the reaction between 3,5-diphenylpyrazole (1a) and diphenyliodonium triflate
(2a) as our model system. Three possible pathways can be devised for the arylation reaction
which are displayed in Figure 1. All the three pathways start with the formation of the T-shape
adduct from the substrate and the iodonium cation in line with earlier predictions.10,11,17,19 At
variance with other substrates here the iodonium cation forms a bond with the neighbor N atom
which is in fact an efficient Lewis base.25 Along route A the arylation proceeds via a [1,2]-
ACS Paragon Plus Environment

Page 5 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
rearrangement which is followed by the deprotonation of the neighbor N atom by NH3. According
to mechanism B the adduct is formed with the N atom of the acidic NH moiety and then it
undergoes a [2,2]-rearrangement. The proton is subsequently transferred to NH3. Along route C
the adduct first undergoes a deprotonation by the base NH3 followed by the [2,2]-rearrangement
and the release of phenyl-iodide.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. Free energy profiles for paths A and B constructed from solvent corrected Gibbs free energies. Red: path
A; green: path B. Values are in kcal/mol.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 19
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3. Free energy profiles for path C obtained from solvent corrected Gibbs free energy values. Red curve: direct
deprotonation of 1a. Green curve: adduct formation, deprotonation and aryl group migration occuring in DCE. Blue
curve: same reaction steps with transfer of NH4+ and triflate anion to the aqueous phase. Values are in kcal/mol.
Figure 2 shows the calculated free energy profiles for routes A and B. On both paths the first
step is the formation of adduct 3a from the pyrazole substrate and the iodonium cation. Then the
N-arylation by [1,2]-rearrangement goes through a 38.9 kcal/mol free energy barrier, whereas the
[2,2]-rearrangement on path B has a somewhat higher, 45.0 kcal/mol barrier. In the last step the
intermediates are deprotonated by NH3 yielding product 5a. The profiles show a significantly
exergonic reaction. On the other hand the barriers are not compatible with the mild experimental
conditions and suggest that the reaction follows another mechanism.26 Note that both paths A and
B indicate that the deprotonation of the cationic intermediates is a very favorable process. In fact
this is the key for the favorable pathway. Figure 3 shows three variants of path C where the
ACS Paragon Plus Environment

Page 7 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
deprotonation preceeds the N-arylation step. Deprotonation of the reactant pyrazole molecule is
not favorable (+26.4 kcal/mol endergonicity). On the other hand, deprotonation of intermediate
3a needs a considerably smaller, 19.0 kcal/mol free energy investment which implies that the
adduct formation increases remarkably the acidity of the neighbor N-H moiety.25 This can be due
to the extra positive charge carried by the iodonium cation which induces a limited
destabilization to the neighbor N-H moiety. A subsequent N-arylation would require an additional
21.9 kcal/mol free energy investment to go through the activation barrier of 40.9 kcal/mol. After
passing the barrier the reaction is accompanied by a large free energy release due to the formation
of iodobenzene and the N-aryl bond. The final part of the reaction energy is recovered when the
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
byproducts NH4 and triflate counteranion are transferred from the organic phase to the aqueous
phase.
A crucial observation is that aqueous solvation of the ionic byproducts can occur earlier along
the paths and in fact this can remarkably improve the barrier along route C. Indeed, transfer of the
ion pair to the aqueous phase is an exergonic process with -15.5 kcal/mol free energy. As Figure 3
shows, when this process is taken into account at the deprotonation stage, the barrier of the N-
arylation is only 25.4 kcal/mol which explains the experimental observations.
The importance of the ammonia in the N-arylation process was also proved experimentally.
When the N-arylation of 3,5-diphenylpyrazole was performed with mesitylphenyliodonium
triflate in the absence of ammonia solution, the reaction was significantly slower (18%
conversion after 4 hours at 25 °C) and gave N-phenyl pyrazole as product instead of the N-
mesityl derivative. Without the application of external base the pyrazole itself can serve as
deprotonating agent for adduct 3a in the transformation. Due to the steric hindrance between
intermediate 3a and an additional pyrazole molecule, the deprotonation is slower and the transfer
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 19
1
2
3
4
5
6
7
8
9
of the less bulky phenyl group is favored over the mesityl group.27 The protonated pyrazole is not
capable to accept iodonium salt, therefore it could not take part in the desired arylation. This
limits the amount of the reactant, and in turn contributes to the slower reaction progress and the
low conversion.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
On the basis of profile C we can formulate the following mechanistic picture. The reaction
starts with the association of the iodonium cation with a neighbor nucleophilic, ie. Lewis base site
forming a T-shape adduct. The arylation takes place on the heteroatom carrying the acidic proton.
The transfer of one of the aryl ligands is the rate detemining step. It is preceded by the
deprotonation of the complex. The main motif of this mechanism is the consecutive actions of the
neighbor Lewis base and Brønsted acid centers of the substrate: they enable a more favorable 4-
membered cyclic TS, as opposed to a 3-membered TS in the less favorable pathway. At variance
with other methods employing strong bases here the presence of aqueous phase assists to stabilize
the intermediate undergoing the intramolecular arylation.
Figure 4. Theoretical versus experimental ΔΔG# of the Ν-arylation of 3,5-diphenylpyrazole with unsymmetric
iodonium salts. ΔΔG# is the difference between the activation free energies of the two possible arylations.29 Only
those reactions are included where both products have been observed. The linear regression line is red. The
experimental error bar (± 0.1 kcal/mol) is derived from an estimated 5% concentration gross uncertainty of the
experimental determination of the final concentration ratios. The theoretical error bar has been set to ± 0.8 kcal/mol
ACS Paragon Plus Environment

Page 9 of 19
The Journal of Organic Chemistry
1
2
3
4
5
which is a typical uncertainty for solvent models.30 A more elaborated error analysis is given in the SI. Colored data
points are explained in the text.
6
7
8
9
The high exergonicity and the moderate barrier indicate that the selectivity of the arylation is
kinetic in origin. To test this hypothesis, we have considered a large body of experimentally
observed arylation reactions of 3,5-diphenylpyrazole with unsymmetric diaryliodonium salts and
calculated their free energy barriers.28 Comparison of the theoretical predictions with
experimental observations in terms of activation free energy differences is plotted out on Figure
4. The plot is somewhat scattered, mainly due to the potential errors in the calculated values.30 To
illustrate the concept of this plot we highlighted two data-points. The orange (horizontal hatched)
data point represents the selectivity between p-Br-phenyl and phenyl groups where the
experimental product ratio is 1:1, although the theory predicted a small, 0.49 kcal/mol activation
energy difference favoring arylation by the p-Br-Ph group. In contrast, the green (vertical
hatched) data point shows that both experiment and theory predict in nice accord high selectivity
for o-Br-phenyl group with respect to phenyl group (experimental product ratio is 9:1 which is
equivalent to 1.30 kcal/mol barrier difference while the theory predicts 2.37 kcal/mol). Overall
we see that our methodology has a general tendency to slightly overestimate the experimental
selectivities. This implies that we can confidently predict the high selectivity cases, whereas in
the less selective cases the uncertainty is relatively larger. With that in mind we can conclude that
the chemoselectivity observed here is indeed kinetically controlled, in line with earlier findings11
for other substrates.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 19
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 5. Arylation products obtained from the N-arylation of various heterocycles with phenyl(mesityl)iodonium
triflate and the experimental conditions. The arylations of the present work have been performed in 1:1 toluene –
25% NH3 solution. The calculated activation barriers (kcal/mol), conversions, product ratio and isolated yields in
parentheses are indicated.
The mechanistic pattern indicates that other substrates featuring a strategically positioned
Lewis base (nucleophilic) and Brønsted acidic centers in close vicinity can also undergo facile
arylation with diaryliodonium salts under mild conditions with the same mechanism. This
ACS Paragon Plus Environment

Page 11 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
prediction has been tested on a limited set of substrates (Figure 5) by calculations and also
confirmed experimentally. Selection of these substrates was guided by the criterion to exclude the
ambiguity brought by tautomerism between the two vicinal N-sites of the original pyrazole
frames. Figure 5 shows that the new substrates can be arylated in acceptable to good yield with
the present methods. On the other hand indole, where this mechanism cannot work, is inactive in
this reaction.31 In addition we invoked here three recent examples from the literature10,14,16 with
C, N and O-functionalization, where the present mechanism can be postulated, although the
experimental conditions vary considerably (Fig. 6). These examples demonstrate that detailed
insight into the mechanism efficiently helps in extending the scope of the method. However, we
note that further optimization of the conditions for the new substrates is necessary for amplifying
the potential of this synthetic strategy.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 6. Recent literature examples where the present mechanism was postulated10,14 or it can be assumed via the
iminol tautomer.16
CONCLUSIONS
In conclusion, we have successfully explored the reaction mechanism of the N-arylation of
pyrazoles with diaryliodonium salts. We find that the close vicinity of the two N atoms plays a
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 19
1
2
3
4
5
6
7
8
9
crucial role in the mechanism: the nucleophilic (Lewis-base) N-site supports the iodonium ion
while the N atom of the Brønsted acid N-H moiety is arylated. This tandem action enables the
employment of weak, aqueous base in the reaction facilitating the formation of the deprotonated
iodonium substrate precursor for arylation. We have also shown that the mechanistic pattern is
more general and on the basis of the mechanism other substrates could also be identified and
functionalized by unsymmetric diaryliodonium salt under mild conditions.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
EXPERIMENTAL SECTION
General Informations
Unless otherwise indicated, all starting materials were obtained from commercial suppliers, and
were used without further purification. Analytical thin-layer chromatography (TLC) was
performed on pre coated TLC plates with 0.25 mm Kieselgel 60 F254. Visualization was
1
13
19
performed with a 254 nm UV lamp. The H, C and F NMR spectra were recorded in CDCl3,
D3COD, CD3CN and DMSO-d6. Chemical shifts are expressed in parts per million (δ) using
1
13
residual solvent protons as internal standards (δ 7.26 for H, δ 77.0 for C). Coupling constants
(J) are reported in Hertz (Hz). Splitting patterns are designated as s (singlet), d (doublet), t
(triplet), q (quartet), m (multiplet). Combination gas chromatography and low resolution mass
spectrometry was obtained gas chromatograph with 30 m x 0.25 mm column with 0.25 µm HP-
5MS coating, He carrier gas and in Mass Spectrometer with Ion source: EI+, 70eV, 230oC;
interface: 300oC. IR spectra were obtained on a spectrometer equipped with a single-reflection
diamond ATR unit. All melting points were measured and are uncorrected. High-resolution mass
spectra were acquired on a time-of-flight mass spectrometer equipped with a Jet Stream
electrospray ion source in positive ion mode. Injections of 0.1-0.3 µl were directed to the mass
ACS Paragon Plus Environment

Page 13 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
spectrometer at a flow rate 0.5 ml/min (70% acetonitrile-water mixture, 0.1 % formic acid), using
an HPLC system. Jet Stream parameters: drying gas (N2) flow and temperature: 10.0 l/min and
325 °C, respectively; nebulizer gas (N2) pressure: 10 psi; capillary voltage: 4000V; sheath gas
flow and temperature: 325 °C and 7.5 l/min; TOFMS parameters: fragmentor voltage: 120 V;
skimmer potential: 120V; OCT 1 RF Vpp:750 V. Full-scan mass spectra were acquired over the
m/z range 100-2500 at an acquisition rate of 250 ms/spectrum and processed by Agilent
MassHunter B.03.01 software.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General procedure for the synthesis of N-arylated heterocycles
The appropriate N-heterocycle (0.5 mmol, 1.0 equiv), diaryliodonium salt (0.55 mmol, 1.1
equiv), were placed in a 30 ml vial and dissolved in 25w/w% NH3 (aq) solution-toluene 1:1 (20
mL) stirred at RT for the indicated time. The reaction mixture was diluted with CH2Cl2 (10 mL).
The aqueous layer was extracted with CH2Cl2 (2 × 10 mL) and all combined organic phase were
dried over magnesium sulphate. The suspension was then filtered, concentrated in vacuo and
purified by flash chromatography on silicagel in hexane-ethyl acetate eluent, if not noted
otherwise.
Indole: the reaction did not take place even after 96 hours (0% conversion), the starting material
was recovered in 89% (52 mg).
4-Chloro-7-mesityl-7H-pyrrolo[2,3-d]pyrimidine
The general procedure was followed (24 h, 50 °C). GC-MS conversion: 90%, off-white solid (66
1
mg, 0.25 mmol, yield: 49%). Rf.: 0.49 (in hexane:EtOAc 4:1), M.p.: 117-118 °C, H NMR (250
MHz, CDCl3) δ 8.62 (s, 1H), 7.23 (d, J = 3.6 Hz, 1H), 7.04 (s, 2H), 6.81 (d, J = 3.6 Hz, 1H), 2.37
(s, 3H), 1.90 (s, 6H) ppm. 13C NMR (63 MHz, CDCl3) δ 152.77, 151.8, 151.6, 139.9, 136.4,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 19
1
2
3
4
5
6
7
8
9
132.4, 130.8, 129.7, 117.6, 100.8, 21.5, 18.0 ppm. MS (EI, 70 eV): m/z (%): 271 (38, [M+]), 236
(5), 208 (100), 193 (16), 167 (6), 115 (16), 91 (19), 77 (17). IR (ATR), 1585, 1544, 1510, 1488,
1454, 1413, 1354, 1279, 1246, 1208, 1149, 988, 910, 850, 731 cm-1. HRMS calcd for C15H15ClN3
[M+H]+ 272.0949 found 272.0953
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-Chloro-2-mesitylphthalazin-1(2H)-one
The general procedure was followed (16 h, 25 °C) GC-MS conversion: 100%. off-white solid (65
1
mg, 0.22 mmol, yield: 44%). Rf.: 0.37 (in hexane:EtOAc 4:1), M.p.: 143-144 °C, H NMR (250
MHz, CDCl3) δ 8.54 (dd, J = 7.8, 1.5 Hz, 1H), 8.09 (dd, J = 7.5, 1.5 Hz, 1H), 8.04 – 7.81 (m,
13
2H), 7.00 (s, 2H), 2.34 (s, 3H), 2.11 (s, 6H) ppm. C NMR (63 MHz, CDCl3) δ 158.8, 139.4,
138.8, 137.0, 135.3, 134.4, 133.2, 129.7, 129.3, 128.4, 126.3, 21.5, 18.0 ppm. MS (EI, 70 eV):
m/z (%): 298 (39, [M+]), 283 (42), 281 (100), 263 (73), 130 (64), 116 (24), 102 (53), 91 (55) 77
(24). IR (ATR), 1667, 1611, 1581, 1544, 1484, 1454, 1339, 1290, 1272, 1171, 996, 850, 772,
727, 690 cm-1. HRMS calcd for C17H15N2OCl [M+H]+ 299.0946 found 299.0951
1-Mesityl-1H-pyrrolo[2,3-b]pyridine
The general procedure was followed (50 °C, 24 h). GC-MS conversion: 70% after 24 h.
Unseparable mixture of mesityl and phenyl substituted products (product ratio: 11.5:1).
5-Bromo-1-mesityl-1H-pyrrolo[2,3-b]pyridine
The general procedure was followed (50 °C, 24 h). GC-MS conversion: 62% after 24 h.
Unseparable mixture of mesityl and phenyl substituted products (product ratio: 11.5:1).
3-Iodo-1-mesityl-1H-pyrrolo[2,3-b]pyridine
The general procedure was followed. GC-MS conversion: 100% product ratio: 19:1. Yellow
1
solid (80 mg, 0.67 mmol, yield: 67%). Rf.: 0.36 (in hexane:EtOAc 9:1), M.p.: 119-121 °C, H
ACS Paragon Plus Environment

Page 15 of 19
The Journal of Organic Chemistry
1
2
3
4
NMR (250 MHz, CDCl3) δ 8.33 (d, J = 4.7 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.29 (s, 1H), 7.18
5
6
13
(dd, J = 7.9, 4.7 Hz, 1H), 7.03 (s, 2H), 2.36 (s, 3H), 1.92 (s, 6H) ppm. C NMR (63 MHz,
7
8
9
CDCl3) δ 147.7, 145.3, 139.4, 136.9, 133.2, 133.0, 129.9, 129.6, 123.2, 117.3, 55.2, 21.6, 18.1
ppm. MS (EI, 70 eV): m/z (%): 362 (88, [M+]), 235 (96), 220 (100), 205 (43), 119 (29), 110 (56),
91 (31) 77 (27). IR (ATR), 1609, 1590, 1564, 1497, 1479, 1455, 1433, 1406, 1373, 1313, 1301,
1272, 1215, 1197, 1155, 1108, 1029, 1014, 980, 962, 949, 915, 884, 853, 806, 790, 764, 702, 622,
607 cm-1. HRMS calcd for C16H15N2I [M+H]+ 363.0353 found 363.0357
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-Mesityl-1H-benzo[d][1,2,3]triazole and 1-mesityl-2H-benzo[d][1,2,3]triazole32
The general procedure was followed. GC-MS conversion: 100% product ratio: 2N/1N 2:1.
Computational Details
The calculations have been performed using the ωB97X-D range-separated hybrid exchange-
correlation functional by using the Gaussian 09 package.33 The ωB97X-D functional has been
shown to perform remarkably well for noncovalent interactions and thermochemistry.34 Ultrafine
grid has been employed for all calculations. The 3D structures presented in the article have been
visualized by using the Cylview software.35 For geometry optimizations and frequency
calculations we have employed the 6-31+G* basis set (atoms H, C, N, O, F, S, Cl and Br),
whereas for iodine we selected the LanL2DZ basis set completed with a set of polarization and
diffuse functions taken from the corresponding aug-cc-pVDZ-PP basis set.24 Single point
dichloro-ethane or toluene solvated electronic energies have been calculated for the optimized
structures using a larger basis set: LanL2TZ(f) with additional set of polarization and diffuse
functions from the aug-ccpVTZ-PP for iodine and the 6-311++G(3df,3pd) set for all the other
atoms (selection of the solvents follows the experimental conditions). Solvent corrected free
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 19
1
2
3
4
5
6
energies have been calculated within the harmonic oscillator, rigid rotor, ideal gas approximation.
For further computational details and for a discussion of possible error sources see SI.
7
8
9
ASSOCIATED CONTENT
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Supporting Information
The Supporting Information is available: experimental details, chromatograms, NMR spectra and
selectivites, calculation details, stability data, error analysis, activation barriers, XYZ data of the
structures; free of charge on the ACS Publications website at DOI: .
AUTHOR INFORMATION
Corresponding Author
E-mail: stirling.andras@ttk.mta.hu
E-mail: novakz@elte.hu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We acknowledge the computational resources of NIIF, OTKA Grant K116034, the Hungarian
Academy of Sciences (LP2012-48/2012) and we thank Ádám Madarász for fruitful discussions.
REFERENCES
1) General reviews on the synthesis and application of hypervalent iodonium salts: a) Zhdankin V. V.; Stang P. J.
Chem. Rev. 2008, 108, 5299-5358.; b) Zhdankin V. V. Hypervalent Iodine Chemistry, Wiley, Chichester, 2014, pp. 1-
480.; c) Yusubov M. S.; Maskaev A. V.; Zhdankin V. V. ARKIVOC 2011, 370-409.; d) Silva, Jr. L. F.; Olofsson B.
Nat. Prod. Rep. 2011, 28, 1722-1754.; e) Charpentier J.; Früh N.; Togni A. Chem. Rev. 2015, 115, 650-682.; f)
Yoshimura A.; Zhdankin V. V. Chem. Rev. 2016, 116, 3328-3435.
2) Reviews on the synthesis and application of diaryl iodonium salts: a) Merritt E. A.; Olofsson B. Angew. Chem. Int.
Ed. 2009, 48, 9052-9070.; b) Grushin V. V. Chem. Soc. Rev. 2000, 29, 315-324.; c) Olofsson, B. In Current
Developments in Hypervalent Iodine Chemistry (Ed.: T. Wirth); Topics in Current Chemistry, Springer Berlin
Heidelberg, 2015. d) Aradi, K.; Tóth, B. L.; Tolnai, G. L.; Novák, Z. Synlett, 2016, DOI: 10.1055/s-0035-1561369.
ACS Paragon Plus Environment

Page 17 of 19
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
3) a) Kang, Yoon S. K.; Kim Y.-M. Org. Lett., 2001, 3, 2697-2699. b) Vaddula B.; Leazer J.; Varma R. S. Adv. Synth.
Catal. 2012, 354, 986-990. c) Niu H.-Y., Xia C.; Qu G.-R.; Zhang Q.; Jiang Y., Mao R.-Z.; Li D.-Y.; Guo H.-M. Org.
Biomol. Chem. 2011, 9, 5039-5042. d) Zhou T.; Li T.; Chen Z.-C. Helv. Chim. Acta 2005, 88, 290-296. e) Zhou T.;
Chen Z.-C. Synth. Commun. 2002, 32, 903-907. f) Rewcastle G. W.; Denny W. A. Synthesis 1985, 220-222. g)
Scherrer R. A.; Beatty H. R. J. Org. Chem. 1980, 45, 2127-2131. h) Wang L.; Chen Z.-C. J. Chem. Res. Synop. 2000,
2000, 367-369. i) Ackermann L.; Vicente R.; Kapdi A. R. Angew. Chem., Int. Ed. 2009, 48, 9792-9826.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4) Guo F.; Wang L.; Wang P.; Yu J. Han J., Asian J. Org. Chem. 2012, 1, 218-221.
5) Carroll M. A.; Wood R. A. Tetrahedron 2007, 63, 11349-11354.
6) Beringer M. F.; Brierley A.; Drexler M.; Grindler E. M.; Lumpkin C. C. J. Am. Chem. Soc. 1953, 75, 2708-2712.
7) Ghosh R.; Lindstedt E.; Jalalian N. Olofsson B. Chem. Open, 2014, 3, 54-57.
8) a) Wen J.; Zhang R.-Y.; Chen S.-Y.; Zhang J.; Yu X.-Q. J. Org. Chem. 2012, 77, 766-771.; b) Kita, Y.; Dohi, T.
Chem. Record 2015, 15, 886-906.
9) Gonda Zs.; Novák Z. Chem. Eur. J. 2015, 21, 16801-16806.
10) Norrby P.-O.; Petersen T. B.; Bielawski M.; Olofsson B. Chem. Eur. J. 2010, 16, 8251-8254.
11) Malmgren J.; Santoro S.; Jalalian N.; Himo F.; Olofsson B. Chem. Eur. J. 2013, 19, 10334-10342.
12) Oh C. H.; Kim J. S.; Jung H. H. J. Org. Chem. 1999, 64, 1338-1340.
13) Ochiai M.; Kitagawa Y.; Toyonari M. ARKIVOC 2003, 43-48.
14) Tinnis F.; Stridfeldt E.; Lundberg H.; Adolfsson H.; Olofsson B. Org. Lett. 2015, 17, 2688-2691.
15) Shi W.-M.; Ma X.-P.; Pan C.-X.; Su G.-F.; Mo D.-L. J. Org. Chem. 2015, 80, 11175-11183.
16) Mehra M. K.; Tantak M. P.; Kumar I.; Kumar D. Synlett 2015, 27, 604-610.
17) Carroll M. A.; Martin-Santamaria S.; Pike V. W.; Rzepa H. S.; Widdowson D. A. J. Chem. Soc. Perkin Trans.
1999, 2, 2707-2714.
18) Martin-Santamaria S.; Carroll M. A.; Carroll C. M.; Carter C. D.; Rzepa H. S.; Widdowson D. A.; Pike V. W.
Chem. Commun. 2000, 649-650.
19) Pinto de Magalhaes H.; Lüthi H. P.; Togni A. Org. Lett. 2012, 14, 3830-3833.
20) Pinto de Magalhaes H.; Lüthi H. P.; Togni A. J. Org. Chem. 2014, 79, 8374-8382.
21) Iwama T.; Birman V. B.; Kozmin S. A.; Rawal V. H. Org. Lett. 1999, 1, 673-676.
22) Yamada, Y.; Okawara, M. Bull. Chem. Soc. Jpn. 1972, 45, 2515-2519.
23) Tolnai G. L.; Székely A.; Makó Z.; Gáti T.; Daru J.; Bihari T.; Stirling A.; Novák Z. Chem. Commun. 2015, 51,
4488-4491.
24) For further details see the SI.
25) For a discussion of the calculation of the deprotonation barrier see SI.
26) Note that very similar profiles (shown in the SI) are obtained by employing water as solvent for all charged
reactants, intermediates, transition states and ammonia .
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 19
1
2
3
4
5
27) Graphical interpretation is given in the SI.
28) The experimental yields9 and the calculated barriers are listed in the SI.
6
7
8
9
29) The experimentally measured yields are converted to activation energies by assuming the validity of transition
state theory and using the equation: ∆∆ꢀ# = ꢀꢀ!# − ꢀꢀ!# = ꢀꢁ ln !!! , where c1 and c2 are the experimental GC-MS
!
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
yields.
30) Marenich A. V.; Cramer C. J.; Truhlar D. G. J. Chem. Theor. Comp. 2013, 9, 609-620.
31) Arylation of the 3C site would require even a higher, 35 kcal/mol activation free energy.
32) Kulagowski, J. J.; Moody, C. J.; Rees, C. W. J. Chem. Soc. Perkin Trans. 1 1985, 12, 2725-2732.
33) Gaussian 09, Revision D.01, Frisch, M. J. et al. Gaussian, Inc. 2013.
34) a) Chai, J.-D.; Head-Gordon, M. Phys. Chem. Chem. Phys. 2008, 10, 6615– 6620.; b) Grimme, S. Wiley
Interdisc. Rev. Comput. Mol. Sci. 2011, 1, 211– 228.
35) CYLview, 1.0b; Legault, C. Y., University of Sherbrooke, 2009 (http://www.cylview.org)
ACS Paragon Plus Environment