Copper catalysed alkylation of heteroaryl chloride via migratory insertion of carbenes

Article abstract of DOI:10.1016/j.jorganchem.2017.07.006

Cross-coupling reaction involving Cu catalysed carbene migratory insertion with N-tosylhydrazones as the reaction partner with various substituted cyanuric chloride were studied, which has been recognized as a new type of cross-coupling reaction. Cu-carbe

Full text of DOI:10.1016/j.jorganchem.2017.07.006

Accepted Manuscript
Copper catalysed alkylation of heteroaryl chloride via migratory insertion of carbenes
Sulochana S. Mudaliar, Shailesh N. Zala, Kishor H. Chikhalia
PII:
S0022-328X(17)30428-X
10.1016/j.jorganchem.2017.07.006
JOM 20020
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 31 March 2017
Revised Date: 1 June 2017
Accepted Date: 6 July 2017
Please cite this article as: S.S. Mudaliar, S.N. Zala, K.H. Chikhalia, Copper catalysed alkylation of
heteroaryl chloride via migratory insertion of carbenes, Journal of Organometallic Chemistry (2017), doi:
10.1016/j.jorganchem.2017.07.006.
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ACCEPTED MANUSCRIPT
Copper Catalysed Alkylation of Heteroaryl Chloride via
Migratory Insertion of Carbenes.
Sulochana S. Mudaliar,[a] Shailesh N Zala,[b] and Prof. Kishor H. Chikhalia* [a]
Department of Chemistry, School of Science, Gujarat University, Ahmedabad 380009,
Gujarat, India. E-mail: Chikhalia_kh@yahoo.com, Tel. No. 079-26300969
Abstract.
Cross-coupling reaction involving Cu catalysed carbene migratory insertion with N-
tosylhydrazones as the reaction partner with various substituted cyanuric chloride were
studied, which has been recognized as a new type of cross-coupling reaction. Cu-carbene
migratory insertion is proposed to play the key role in this transformation to form C-C bond
from heterohalides with various tosylhydrazones. Salient features of this reactions are (i) no
stoichiometric organometallic reagents are required (ii) less toxic and step economical
reaction (iii) easy to handle, to get moderate to excellent yields. Outcome of this reaction
produces 1,1-heterodiaryl alkanes.
Key Words.
Cross-coupling reaction, Cu-catalyst, Migratory insertion, N-tosylhydrazone, Cyanuric
chloride.
Graphical abstract.
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Introduction.
Tranisition metal catalyzed cross-coupling reactions of hydrazenes have been established as
new tool for the formation of C-C and Carbon-heteroatom bonds.[1,2] Diazo compounds
generates (Pd, Cu, Rh, Ni and Co) metal carbene species under basic conditions and
undergoes diverse chemical reactions.[3] Extensive study has been carried out on transition
metal catalysed reaction of diazo compounds which leads to the development of new
synthetic route in organic synthesis. Diazo compounds are subjected to generate carbene in
situ from the corresponding N-tosylhydrazones, which have been used as coupling partner in
the cross-coupling reactions.[4-6] Here in we report a Cu-catalyzed carbene migratory insertion
of N-tosylhydrazones with substituted heteroaryl chlorides, which resulted 1,1-heterodiaryl
alkane compounds as the final product.
It has been widely studied that Pd catalysed cross-coupling reaction can be appropriately
incorporated with the carbene insertion reaction.[7] With this combinations, novel
transformations that are distinct from both classical cross-coupling and carbene insertion.
Recent studies revealed that this chemistry is not only limited to palladium, but Cu proved to
be the best catalyst in the carbene migratory insertion via cross-coupling reaction, which
gained a great interest in frontiers of synthetic chemistry.[8] Cu-salts possess less toxicity and
also inexpensive, easily available transition metal, which is used as catalyst in various cross-
coupling reactions. Detail study on Cu carbene migratory insertion were given by Jianbo
Wang & co-workers in their catalytic cascade reactions involving metal carbene migratory
insertion [9], also they have premeditated a work on direct benzylation of 1,3-azoles with N-
tosyl hydrazine, by considering Cu as catalyst.[10] Kozlowski and co-workers have given a
detailed overview of cu-catalyzed aerobic organic reactions.[11] Successful migratory insertion
carbene reactants contemplated our interest to get new dimension in paradigm of various
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heterocycles and herein an effort has been made to generate 1,1-heterodiaryl alkane
compounds through Cu catalysed carbene insertion reaction.
Basic approach for the synthesis of 1,1-heterodiaryl alkane follows the Heck reaction[12]
,
Grignard reaction[13], or by way of utilizing organometallic reagents such as organotin,
organomagnesium, organozinc and organolithium etc.[14-17] Use of this organometallic
reagents are toxic, air/moisture sensitive, expensive and also organometallic compounds were
synthesised in harsh condition, which is very challenging in an industrial scale.[18] So for the
advancement of feasible and environmentally compatible chemical methodologies, we
diverged our attention from the general approach of synthesis of heterodiaryl, alkane
compounds to the novel type of transition metal catalysed cross coupling reaction. Having
wide range applications in the synthetic chemistry N-tosylhydrazones had been proved to be
the exceptional coupling partners in the C-H activation reaction. N-tosylhydrazone can be
promptly synthesized from the corresponding ketones and also used as a precursors for the
generation of the metal-carbene complex through the preparation of diazo compounds
without allowing the use of other organometallic reagents.[19-22]
(A). Our Previous work.[23-24]
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(B). Our recent work.
Figure 1. Previous and Recent work of our Group
In our previous work, we have reported palladium catalysed cross coupling reaction of
tautomerizable heterocycles with coupling partners N-tosylhydrazone via C-OH activation
(Fig.1). Palladium catalysed carbene insertion reaction was carried out with tautomeriazbale
heterocycles. β-H elimination was carried out in the process to produce a final prouct, which
resulted with the C=C in the final step of the reaction.
As an advancement from our previous work, here in we are reporting a Cu catalysed carben
migratory insertion for the synthesis of 1,1-heterodiaryl alkane derivatives, which is found
more efficient than the previously existing reports. In our previous work Pd-catalysed
carbene insertion reaction was employed for the synthesis of 1,1, heterodiaryl alkenes, which
was followed through β-H elimination reaction with N-tosylhydrazones and hetero arenol.
Previous works on Cu carbene migratory insertion reactions had been studied extensively
with activation of acidic proton.[25] Our work is distinctive from the earlier studied work in
which C-Cl bond is being activated by employing Cu with Cs2CO3 and NaH. This new
system of alkylation follows Cu-catalyzed cabene migratory insertion involving protonation
under mild condition, use of less toxic transition metal Cu and 1,10-phenanthroline as a
ligand. So we imitated our work by employing Cu to the di-substituted chloro heterocycles s-
triazine. The synthetic strategy is given in the plausible mechanism. The resulted products
were found in the agreement with the desired product.
Result and Discussion.
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To investigate the feasibility of preferred reaction, we strived with cyanuric chloride(1a) as a
basic material and tosylhydrazone(2a) as a model substrate. Our preliminary inspection was
carried out using CuI as catalyst, 1,10pehananthroline as ligand and Cs2CO3&NaH as base,
refluxing temperature condition utilising 1,4-dioxane as solvent and underneath air. The
result which we obtained was formation of aimed product with good yield as it used to be in
blend of alternative unintended spinoff in considerable yield. We also investigated the
formation of product 3a, with different ligands, catalysts, base as well as solvents.
Optimization experiences is recounted in table 1. During the optimization it is observed that
utilization of CuI as catalyst yielded the preferred product 9in acceptable to high yield.
Figure. 2 List of lignds used in the reaction
N
N
N
N
N
2,2'-Bipyridine
Pyridine
1,10-Phenanthroline
O
N
O
N
NO2
H3C
CH3
N
N
N
N
1,10-Phenanthroline-5,6-dione
5-Nitro-1,10-phenanthroline
5,6-Dimethyl-1,10-phenanthroline
As an alternative of CuI, different copper catalyst like CuCl and CuBr have been additionally
employed as effective catalyst but no significant deviation has been observed to CuI.
Employment of Cu(OAc)2 proved to be an in appropriate catalyst for this reaction. Ligands
have been determined to demonstrate a valuable role in the targeted reaction and screening
effect of ligand lead us to conclude that 1,10-phenanthroline proved to be the most productive
amongst other verified ligands equivalent to 2,2’-bipyridine, pyridine, 5,6-dimethyl-1,10-
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phenanthroline, 5-nitro-1,10-phenanthroline. Furthermore, trace amount of yield was observed in
the case of ligand free test.
After the effective optimization of catalyst and ligand we then shifted our attention towards
influence of base and solvents on proposed alkylation reaction. Screening experiences
divulge that Cs2CO3 was once located as most inclined base compared to different viz.
KOtBu, K2CO3 and LiOtBu. Further study reveals that KOtBu, K2CO3 and LiOtBu was
found better for other heterocyclic/non-heterocyclic motif motif but in the present study no
significant result has been observed, even their combination with other base also did not
proved their effectiveness. As it can be observed from table-2.
One more strong base NaH was employed as a part of the following reaction process in which
the base has an significant role. It is understood that NaH being a strong base can easily
replace the Cl atom. Also reaction was carried out without using NaH, which resulted in trace
amount of yield. It is therefore understood that addition of NaH with Cs2CO3 afforded better
to moderate yield.
After the assessment of bases, the solvent effect for1,4-dioxane, THF, DMF and toluene were
consequently examined. Among which 1,4-dioxane resulted better amount yield in
comparison to the other solvents. Our study reveals that on increasing polarity of the solvents
like DMF and THF resulted in poor yield, where as non-polar solvent like toluene resulted
with moderate amount of yield.
Table 1: Reaction Optimizationa
1a
2a
3a
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Entry Catalyst
Ligand
Base
Solvent
Yieldb
1
2
CuI
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
Cs2CO3
1,4-Dioxane 20%
CuI
Cs2CO3+NaH 1,4-Dioxane 79%
Cs2CO3+NaH 1,4-Dioxane 37%
Cs2CO3+NaH 1,4-Dioxane 12%
Cs2CO3+NaH 1,4-Dioxane Trace
Cs2CO3+NaH 1,4-Dioxane 49%
Cs2CO3+NaH 1,4-Dioxane 58%
Cs2CO3+NaH 1,4-Dioxane 63%
Cs2CO3+NaH 1,4-Dioxane 55%
Cs2CO3+NaH 1,4-Dioxane 43%
KOtBu+NaH 1,4-Dioxane Trace
LiOtBu+NaH 1,4-Dioxane Trace
K2CO3+NaH 1,4-Dioxane 30%
3
CuBr
CuCl
4
5
Cu(OAC)2 1,10-Phenathroline
6
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
Pyridine
7
2,2’Bipyridine
8
1,10-Phenanthroline-5,6-dimethyl
1,10-Phenanthroline-5,6-dione
5-Nitro-1,10-phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
9
10
11
12
13
14
15
16
Cs2CO3+NaH THF
Cs2CO3+NaH Toluene
Cs2CO3+NaH DMF
70%
59%
61%
aReaction condition:Catalyst: 25mol%, ligand: 20 mol%, 1a: 1.0 mmol (0.50 g), 2a: 0.5mmol (0.41g),
b
base:Cs2CO3 + NaH 2.5 equivalent, solvent: 5 ml per mmol. Under air for 12 hours. Isolated Yield.
After the effective achievement of optimistic result of outcome of the reaction, we th
Investigated substrate scope of the reaction with different derivatives of sterically hindered
tosylhydrazones and diverse cyanuric chloride derivatives engaging a feasible catalytic
system, the obtained results are shown in table 2 and 3. Results of the reaction outcomes were
shown in table 2 & 3 suggests that the catalytic system developed in the reaction are suitable
for a wide range of coupling partners, such as different hetero halides with substituted N-
tosylhydrazones. Based on the results obtained it is being concluded that N-tosylhydrazones
containing both electron withdrawing groups and electron donating groups resulted moderate
to good amount of yields, but more significantly tosylhydrazones with electron with drawing
group appeared with less yield to the others.
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In order to enhance the substrate scope, we checked the feasibility of the reaction with
structurally altered hetero halides like quinoline, quinazoline,thiophenes, quinaoxaline,
pyridazines and N-tosylhydrazones. The acquired resulted are summarized in the table 3.
Table 2: Scope of the reaction with variety of Cyanuric chloride and N-tosylhydrazonea
R2
R2
NNHTs
N
N
CuI, 1,10ꢀphenanthroline
N
N
+
R
R'
R'
Cs2CO3, NaH
R1
N
R1
1a
N
X
dioxane, 110°C
R
2a
3a
1 (a-g)
2(a-g)
3(a-g)
Yieldb
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Table 3: Scope of the reaction with variety ofheteroaryl amines and N-tosylhydrazones.
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2(b-k)
3(f-o)
Yieldb
aReaction condition:Catalyst: 25 mol%, ligand: 20 mol%, 1a: 1.0 mmol (0.50 g), 2a: 0.5
mmol (0.41 g), base:Cs2CO3 + NaH 2.5 equivalent, solvent: 5 ml per mmol. Under air for 12
b
hours. Isolated Yield.
On the premise of accomplished outcome and also the literature survey[26-30], of
related reaction, a tentative reaction mechanism of copper catalysed carbene migratory
insertion reaction of 2,4-dimethoxy-6-chloro s-triazine with N-tosylhydrazone is drafted out
as under in Figure 3. Initial coupling reaction between Cu catalyst (A) and the primary
compound of 2,4 dimethoxy-6-chloro s-triazine carried out in the presnence of base and
ligand, by which aryl copper complex was generated(B) Diazo compounds were generated
form N-tosylhydrazone in the presence of base by in situ formation(C). The generated diazo
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compound is inserted in the aryl copper complex (B) to afford the intermediate C, which than
undergoes a carbene migration producing alkane complex (E). Protonation was carried out in
the final step to form the desired product regenerating the CuI catalyst.
Fig. 3: Plausible Mechanism
Conclusion:
In conclusion, we have developed new and feasible method from the commercially available
compound s-triazine
for the synthesis of 1,1-heterodiaryl alkane compounds by Cu
catalyzed carbene migratory insertion, which is environmentally benign, less toxic, cost
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effective. The significant feature of this reaction is that C-Cl bond was activated using Cu-
catalyst has hitherto unreported on this motif. Nevertheless some reports are available only on
C-H activation using Cu catalyst for carbene migratory insertion. The method was applied on
different heterohalide compounds with diverse N-tosylhydrazone derived from ketones. The
said method is proved very effective in the preparation of 1,1-heterodiaryl alkanes than the
other traditional method.
Acknowledgements:
The authors are thankful to Department of Chemistry, Gujarat University, Ahmedabad for all
support and facilities. Authors are thankful to the Oxygen Healthcare for spectral analysis and
GUJCOST for providing financial assistance.
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