The effect of substrate structure on the direction of cyclization of ortho-alkynylbenzene diazonium salts

Article abstract of DOI:10.1016/j.tetlet.2009.10.078

The cyclization of ortho-(arylethynyl)benzene diazonium salts (the Richter reaction) is studied. A reaction mechanism, which differs radically from that reported earlier is proposed and substantiated by experimental data and quantum-chemical calculations.

Full text of DOI:10.1016/j.tetlet.2009.10.078

Tetrahedron Letters 51 (2010) 67–69
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Tetrahedron Letters
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The effect of substrate structure on the direction of cyclization
of ortho-alkynylbenzene diazonium salts
*
Lidiya G. Fedenok , Mark S. Shvartsberg, Valentina S. Bashurova, George A. Bogdanchikov
Institute of Chemical Kinetics and Combustion, Siberian Branch of Russian Academy of Sciences, Instituskaya 3, Novosibirsk 630090, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 May 2009
Revised 9 October 2009
Accepted 19 October 2009
Available online 29 October 2009
The cyclization of ortho-(arylethynyl)benzene diazonium salts (the Richter reaction) is studied. A reaction
mechanism, which differs radically from that reported earlier is proposed and substantiated by experi-
mental data and quantum-chemical calculations.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Cyclization
Mechanism
ortho-Alkynylbenzene diazonium salts
Indazoles
Cinnolines
The cyclization of ortho-alkynylbenzene diazonium chlorides
(the Richter reaction) has been used as a method for the prepara-
tion of cinnoline derivatives.1,2 In a previous Letter, we reported
that in some cases, this reaction proceeds via five-membered
ring-closure to yield 3-(acyl)indazole derivatives 1 (Scheme 1).3
This reaction is favored by strong +M functional groups at position
4 of the phenyl ring of the acetylenic substituent. However, the
cyclization of diazonium salts 2, containing acceptor, neutral, or
weak donor substituents, leads to chlorocinnoline derivatives
4d–f under the same conditions (Scheme 1).3,4
The goal of the present work is to elucidate the reasons for the
different reaction pathways. According to literature data, the
mechanism of the Richter reaction is interpreted as a one-step pro-
cess.2,5,6 It involves intramolecular coordination of the diazonium
group with the b-carbon of the acetylenic substituent together
and expands to a six-membered ring in the other case. In addition,
the five-membered heterocyclic product contains no Cl atom,
although the reaction proceeds under mild conditions in the
presence of excess Clꢀ. In order to investigate these points, we
calculated the Mulliken charge distribution over carbon atoms
C-1, C-2, and C-3 (Fig. 1) in substrates 2a–f, employing the AM1
technique7 using the MOPAC program.8 To estimate the electronic
properties of the substituents, the electrophilic constants rþp were
used (Table 1).
Analysis of the calculated data shows that the triple bond polar-
ization increases with enhancement of the electron-donating prop-
erties of the substituents (Table 2). Simultaneously, the electron
density on C-3 increases. As follows from Table 2, the total charge
on all three atoms is negative and almost doubles from 2f to 2a.
The increase in the electron density on C-1 and C-3 hinders the ap-
proach of the Clꢀ nucleophile.
with simultaneous attack of the nucleophile on the a-carbon. Chlo-
ride usually plays the role of nucleophile, although participation of
water as the nucleophile cannot be excluded. This theory, however,
gives rise to doubts, as it assumes the possibility of intramolecular
interaction between the linear and spatially distant diazo- and
ethynyl groups. It is reasonable to assume that the process is initi-
ated by the nucleophile, which attacks the b-carbon rather than the
At the same time, this charge distribution can favor interaction
between the triple bond and a molecule of water. Diazotization of
anilines 3a–f and cyclization of the corresponding diazonium sul-
fates 5a–f in dilute sulfuric acid were studied to elucidate informa-
tion on the cyclization of vic-(alkynyl)benzene diazonium salts
with participation of water as the nucleophile. The method of sep-
arating the diazotization and cyclization steps, as elaborated by us
earlier,3,4 was used. Diazonium salts 5a–f were cyclized in aqueous
H2SO4 of various concentrations at 25 °C and 45 °C. The following
were established:
a-carbon of the triple bond. Evidently, this interaction leads to the
formation of a five-membered ring. If this is the case, it is necessary
to understand why the five-membered ring is formed in one case
1. Diazonium salts 5a–c are cyclized to 3-benzoylindazoles 1a–c
at the same rate as 2a–c in 20% NaCl (ꢁ5 min, 25 °C).
* Corresponding author. Tel.: +7 (383) 3333 349; fax: +7 (383) 3307 350.
E-mail address: fedenok@kinetics.nsc.ru (L.G. Fedenok).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.078

68
L. G. Fedenok et al. / Tetrahedron Letters 51 (2010) 67–69
COC6H4R
25 oC; 5 min
N
N
H
78-85%
C6H4R
C6H4R
1a-c
R = NMe2 (a); OMe (b); NHCOMe (c)
NaNO2; HCl
20% NaCl
Cl
C6H4R
NH2
N
3a-f
2a-f
Cl
N
45 oC; 60-90 min
70-85%
N
N
4d-f
R = OCOMe (d); H (e); NO2 (f)
Scheme 1.
Table 2
Charge distribution on C-1, C-2, and C-3 in diazonium cations 2a–f
2
3
1
Compound
dꢀC-1
d+C-2
dꢀC-3
Total charge on C-1, C-2, C-3
2a
2b
2c
2d
2e
2f
0.32
0.30
0.29
0.28
0.28
0.24
0.12
0.10
0.10
0.09
0.09
0.05
0.15
0.10
0.09
0.07
0.05
0.00
ꢀ0.35
ꢀ0.30
ꢀ0.28
ꢀ0.26
ꢀ0.24
ꢀ0.19
N
N
Figure 1. Carbon atom numbering of the diazonium cation.
hydroxycinnoline 6f. Diazonium salts 5d, e form a mixture of
1 and 6 in a ratio of 1:2.
Table 1
The electrophilic constants rþp of the substituents in 2a–f9
3. The rate of cyclization of all the compounds of a series is inde-
pendent of the sulfuric acid concentration.
R
NMe2 (2a)
OMe (2b)
ꢀ0.78
NHAc (2c)
ꢀ0.60
OAc (2d)
ꢀ0.19
H (2e)
NO2 (2f)
rþp ꢀ1.70
0
+0.79
Experimental data are in fair agreement with the proposed
mechanism presented in Scheme 2. It includes addition of water to
the alkyne triple bond and subsequent cyclization to form cationic
intermediate 8 containing a five-membered heterocycle. Scheme 2
also shows the transformations of substrates 5b and 5f having
2. The cyclization of diazonium salts 5d–f is 10 times slower than
that of 2d–f in 20% NaCl (ꢁ10 h, 45 °C). The cyclization of 5f
affords the six-membered heterocycle, 3-(4-nitrophenyl)-4-
OH
H
H
R
C
R
R
H2O
N
OH
A
N
N
N
A
N
A
N
5b,f
8b
7b,f
8b,f
O
H
COR
N
R
N
N
N
H
1b
9b
OH
C
H
N
H
OH
N
H
OH
OH
R
R
R
R
N
N
N
N
N
A
A
N
A
10f
6f
8f
R = p-MeOC6H4 (b), p-NO2C6H4 (f)
A = HSO4
Scheme 2. A mechanism for the cyclization of diazonium salts 5b and 5f in H2SO4.

L. G. Fedenok et al. / Tetrahedron Letters 51 (2010) 67–69
69
Table 3
The values of
NMe2
D
H1 and
DH2 for the cyclization of 5a–f
Compound
5a
5b
5c
5d
5e
5f
H
D
D
H1 kcal/mol
H2 kcal/mol
ꢀ19.5
ꢀ12.9
ꢀ15.1
ꢀ11.4
ꢀ5.1
+1.3
ꢀ0.37
+3.1
+12.3
+14.6
+10.1
+4.7
OH
N
10a
N
H,
kcal/mol
Figure 3. The assumed structure of cation 10a.
8f
272.5
10f
272.2
5f + H2O
271.2
Table 4
The charge (d+) on C-2 of cyclic cations 8a–f
6f
60.1
Compound
8a
8b
8c
8d
8e
8f
d+C-2
0.13
0.34
0.33
0.35
0.40
0.41
5b + H2O
220.6
10b
220.0
by 12.3 kcal/mol. Therefore it does not isomerize into 10b, but is
stabilized by elimination of H+ from the hydroxy group to give ke-
tone 9b. After tautomerization, 9b is transformed into the final sta-
ble 3-(4-methoxybenzoyl)indazole product 1b. In contrast, the
distribution of charges in cation 8f favors rearrangement, resulting
in heterocycle expansion. A subsequent 1,2-shift of the hydroxy
group and aromatization lead to the final product, 4-hydroxycinn-
H
1
H
2
8b
207.7
9b
1b
44.0
45.8
oline 6f. Table 3 lists the enthalpy differences (
tion of the five- and six-membered cations. We propose that
can be used as a parameter for prediction of the direction of cycli-
zation. It is interesting that H2 for the substrate with the NMe2
D
H2) for the forma-
reaction coordinate
D
H2
Figure 2. Thermodynamic characteristics for the cyclizations of 5b and 5f in H2SO4.
D
substituent is low. This is probably due to the NMe2 group being
a strong electron-donor, which can stabilize the six-membered
cyclic cation 10a by forming a bridged structure (Fig. 3).
Nevertheless, indazole 1a is the sole product of cyclization of
diazonium salt 5a. Expansion of the pyrazole ring in 8a is appar-
ently hampered by the low value of d+ on C-2 in 8a (Table 4).
Hence, the direction of cyclization can be predicted by taking into
substituents of opposite electronic character (OMe, NO2). In both
cases, the reaction is regioselective, that is, 5b only produces the
five-membered pyrazole and 5f the six-membered pyridazine.
Calculations using the same technique AM1 indicate that the
formation of adducts 7a–f from diazonium salts 5a–f is thermody-
namically advantageous. The energy gain in the series of substrates
varies from 13 to 25 kcal/mol. The addition of water changes the
linear geometry of the acetylenic substituents and the reaction
account both
DH2 and d+ on C-2 in cation 8.
In conclusion, this study on the cyclization of ortho-(arylethy-
nyl)benzene diazonium salts proposes a new cyclization mecha-
nism, which differs radically from that reported earlier. The new
mechanism explains the possibility of the formation of both cinn-
olines and indazoles in the Richter reaction. The ability to predict
the mode of cyclization by means of simple quantum-chemical cal-
culations was demonstrated.
centers approach each other leading to cyclization at the a-carbon
atom of the multiple bond. Table 3 summarizes the enthalpy val-
ues for the transformation of diazonium cations 5a–f into cyclic
cations 8a–f
(DH1). DH1 varies within a wide range from
+1.3 kcal/mol for 5f to ꢀ19.5 kcal/mol for 5a. It is likely, that in this
case, the thermodynamic characteristics of the process correlate
with the values of the activation barriers, thereby determining its
kinetic characteristics.
Supplementary data
This assumption is in agreement with the fact that the reactivity
of the substrates varies in parallel with the change in reaction en-
thalpy. Further transformations of cyclic cations 8b and 8f depend
on the electronic character of the R substituent. Cation 8b main-
tains the five-membered heterocycle, while cation 8f isomerizes
to form the six-membered product (Scheme 2). It should be noted
that the final products, containing the six-membered heterocycle,
are always on average 25 kcal/mol more stable than the reaction
products containing the five-membered heterocycle. Nevertheless,
the cyclization of diazonium salts 5a–c yields reaction products
containing five-membered heterocycles. The reason for this can
be explained by the difference in the energy profiles of the trans-
formation of diazonium salts 5b and 5f as shown in Figure 2. The
direction of the process is likely to depend on the comparative
stability of cations 8 and 10. Due to conjugation with the elec-
tron-donating methoxy group, cation 8b is more stable than 10b
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.10.078.
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