Transition metal and base free coupling of N-tosylhydrazones with 1,3-dicarbonyl compound

Article abstract of DOI:10.1016/j.tetlet.2017.02.001

N-tosylhydrazones derived from a wide variety of aryl, alkyl and heteroaryl aldehydes undergo smooth coupling with 5,5-dimethylcyclohexane-1,3-dione under transition metal and base free conditions to generate tetraketo compounds in high yields. In presenc

Full text of DOI:10.1016/j.tetlet.2017.02.001

Accepted Manuscript
Transition metal and base free coupling of N-tosylhydrazones with 1,3-dicar-
bonyl compound
Deepika Choudhary, Chanchal Agrawal, Vineeta Khatri, Ranjit Thakuria,
Ashok K. Basak
PII:
S0040-4039(17)30166-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.02.001
TETL 48612
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
16 December 2016
31 January 2017
1 February 2017
Please cite this article as: Choudhary, D., Agrawal, C., Khatri, V., Thakuria, R., Basak, A.K., Transition metal and
base free coupling of N-tosylhydrazones with 1,3-dicarbonyl compound, Tetrahedron Letters (2017), doi: http://
dx.doi.org/10.1016/j.tetlet.2017.02.001
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Graphical Abstract
.
Transition metal and base free coupling of
N-tosylhydrazones with 1,3-dicarbonyl
compound
Deepika Choudhary, Chanchal Agrawal, Vineeta Khatri, Ranjit Thakuria and Ashok K. Basak

1
Tetrahedron Letters
Transition metal and base free coupling of N-tosylhydrazones with 1,3-dicarbonyl
compound
Deepika Choudhary,a Chanchal Agrawal,a Vineeta Khatri,a Ranjit Thakuriab and Ashok K. Basak*a
aDepartment of Chemistry, University of Rajasthan, JLN Marg, Jaipur-302004, Rajasthan, India
bDepartment of Chemistry, Gauhati University, Guwahati-781014, Assam, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
N-tosylhydrazones derived from a wide variety of aryl, alkyl and heteroaryl aldehydes undergo
smooth coupling with 5,5-dimethylcyclohexane-1,3-dione under transition metal and base free
conditions to generate tetraketo compounds in high yields. In presence of a base, the coupling
reaction generates β-keto enol ether as the major product in a polar aprotic solvent. N-
Tosylhydrazone can also be converted to xanthenedione in high yields in one-pot operation
under mild acidic conditions.
Available online
Keywords:
N-Tosylhydrazone
Tetraketone
2009 Elsevier Ltd. All rights reserved.
β-Keto enol ether
Transition metal free C-O coupling
Xanthenedione
N-Tosylhydrazones have emerged as useful reagents for
important organic transformations.1 They are stable at room
temperature and can be generated easily from carbonyl
compounds. When treated with a base, N-tosylhydrazones
generate diazo compounds via Bamford-Stevens reaction.2 Cross-
coupling of the diazo intermediates with carbon3 and
heteronucleophiles such as nitrogen,4 oxygen5 and sulphur6 have
been extensively studied by various research groups. Important
examples of carbon nucleophiles include activated aryl group,
alkyne and heteroaomatics. These coupling reactions often
require
a
transition metal catalyst which generates
metallocarbene complex responsible for effective cross-coupling
reactions. In recent years, transition metal free cross-coupling
reactions have gained significant importance.7 Since the report of
metal free coupling of N-tosylhydrazones with boronic acid3b and
hydroxyl compounds5 by Valdés and co-workers, the application
of N-tosylhydrazones for various coupling reactions has
improved significantly. In continuation with our on-going
research interest in new synthetic applications of N-
tosylhydrazones,8 herein we report the coupling of a variety of
N-tosylhydrazones with 5,5-dimethylcyclohexane-1,3-dione
under transition metal free conditions.9
Our hypothesis of the coupling reaction is presented in
Scheme 1. Coupling of the diazo intermediate with a 1,3-
dicarbonyl compound would lead to new C-C or C-O bond
formation. Our investigation started with N-tosylhydrazone 1a
derived from benzaldehyde. Compound 1a was treated with
dimedone in presence of a base in different solvents. As listed in
Table 1, reaction in presence of 1.1 eq of K2CO3 in DMF
generated O-alkylated product 3 in 28% yields
along with the tetraketo compound 5a (entry a, Table 1). The
mono C-alkylated product 4 was not obtained under these
conditions. Similar results were obtained when the reaction was
carried out using Cs2CO3 as a base. Reactions in polar-aprotic
solvents such as DMSO, DMPU, NMP, HMPA also resulted into
low yield of O-alkylated product (entries c-f, Table 1). We were

2
tosylhydrazone derived from 2,4-dimethoxybenzaldehyde
unable to find suitable conditions to generate the O-alkylated
product in high yields.10 When the reaction was carried out using
2.0 equivalent of dimedone in DMF, O-alkylated product was
obtained in 45% yields along with 34% of the tetraketo
compound 5a and 14% yields of the mono C-alkylated product 4
(entry g, Table 1). In dioxane, the reaction resulted into 30%
yields of O-alkylated product along with 48% yields of the
tetraketo compound 5a (entry h, Table 1). When the reaction was
carried out in toluene, tetraketo compound was obtained in 82%
yields along with trace amount of the O-alkylated product (entry
i, Table 1). The reaction resulted into high yield
underwent smooth coupling with dimedone and the
corresponding tetraketo compound 5f was obtained in 80%
yields. N-Tosylhydrazone derived from cinnamaldehyde
produced trace amount of product 5g. Knoevenagel adduct 9 was
isolated in 76% yields after column chromatography.
Condensation of N-tosylhydrazone derived from α-
naphthaldehyde with dimedone was slow and required 4 hours
for completion to give 84% yield of the corresponding tetraketo
compound 5h. N-tosylhydrazones derived from heteroaryl
aldehydes also underwent smooth coupling with dimedone to
generate the corresponding tetraketo compounds in high yields.
Substrate derived from N-Boc 5-bromo indole-3- carboxaldehyde
generated the corresponding tetraketo compound 5i in 82%
yields. Reactions of thiophene-2-carboxaldehyde and furfuryl-2-
carboxaldehyde derived substrates were complete within 30
minutes and generated the corresponding tetraketo compounds 5j
and 5k in 84% and 80% yields respectively. Reaction of N-
tosylhydrazone derived from pyridine 3-carboxaldehyde required
2 hours for completion to generate tetraketo compound 5l in 83%
yields. Substrate derived from cyclohexane carboxaldehyde
underwent smooth coupling with dimedone generating tetraketo
compound 5m in 85% yields. Besides dimedone, we also tested a
few 1,3-dicarbonyl compounds for the base free coupling
reaction with N-tosylhydrazone 1a. Cyclohexane 1,3-dione
underwent smooth coupling with N-toshylhydrazone 1a to
generate tetraketo compound 5n in 86% yields. However, Acetyl
acetone failed to generate measurable amount of product even
after heating for 12 hours. Dibenzoylmethane and ethyl
acetoacetate also failed to undergo effective coupling with N-
tosylhydrazone 1a possibly due to stabilization of the enol forms
by intramolecular H-bonding.
The plausible mechanism of base free coupling of N-
tosylhydrazone with dimedone is depicted in Scheme 2.
Nucleophilic addition of dimedone to the N-tosylhydrazone 1a
leads to the intermediate
7
which would decompose
intramolecularly to generate the Knoevenagel adduct 8. In case of
N-tosylhydrazone 1g derived from cinnamaldehyde, the highly
conjugated Knoevenagel adduct 9 could be isolated in good
yields (Scheme 3). The Knoevenagel adduct 8 reacts with a
second molecule of dimedone to generate the tetraketo compound
5a. Except cinnamaldehyde derived N-tosylhydrazone, we did
not observe the Knoevenagel adduct intermediate in the coupling
reactions.
of the tetraketo compound when carried out in presence of 0.5
equivalent of K2CO3 as a base. In absence of base, the reaction
required 30 minutes for completion to give 90% yields of the
tetraketo compound 5a (entry k, Table 1).
To find out the scope of the base free coupling of N-
tosylhydrazones with 1,3-diketones for the synthesis of tetraketo
compounds, we tested several N-tosylhydrazones derived from
aliphatic, aromatic, heteroaromatic and α,β-unsaturated aldehydes
and the results are presented in Table 2. Aromatic aldehyde
derived substrates provided high yields of the tetraketo
compounds. Substrates containing electron withdrawing groups
in the benzene ring provided tetraketo compounds in high yields
in short reaction time. N-Tosylhydrazone derived from 4-hydroxy
benzaldehyde provided corresponding tetraketo compound 5d in
84% yields. The reaction required 4 hours for completion.
However, no coupling was observed with N-tosylhydrazone
derived from o-hydroxybenzaldehyde. On the other hand, N-
The structure of compound 5a has been confirmed by single
crystal X-ray studies (Figure 1). The ‘Y’ shaped three
dimensional structure of compound 5a is stabilized by
intramolecular H-bonding between O-atom of carbonyl group
and H-atom of enolic hydroxyl group.11

3
References and notes
1. For recent reviews, see: a) Barluenga J, Valdés C. Angew Chem
Int Ed. 2011;50:7486; Angew Chem. 2011;123:7626; b) Shao Z,
Zhang H. Chem Soc Rev. 2012; 41:560; c) Xiao Q, Zhang Y,
Wang JB. Acc Chem Res. 2013;46:236. d) Jadhav AP, Ray D, Rao
VUB, Singh RP. Eur J Org Chem. 2016;2369.
2. Bamford WR, Stevens TS. J Chem Soc. 1952;4735.
Figure 1: ORTEP diagram of compound 5a
3. For selected examples, see: a) Aggarwal VK, Alonso E, Bae I,
Hynd G, Lydon KM, Palmer MJ, Patel M, Porcelloni M,
Richardson J, Stenson RA, Studley JR, Vasse J-L, Winn CL, J Am
Chem Soc. 2003;125:10926; b) Barluenga J, Tomás-Gamasa M,
Aznar F, Valdés C. Nat Chem. 2009;1:494; c) Barluenga J,
Escribano M, Aznar F, Valdés C. Angew Chem Int Ed.
2010;49:6856; Angew Chem. 2010;122:7008; d) Zhou L, Ye F,
Zhang Y, Wang J. J Am Chem Soc. 2010;132:13590; e) Barluenga
J, Florentino L, Aznar F, Valdés C. Org Lett. 2011;13:510; f) Xiao
Q, Xia Y, Li H, Zhang Y, Wang J. Angew Chem Int Ed.
2011;50:1114; Angew Chem. 2011;123:1146; g) Zhao X, Wu G,
Zhang Y, Wang J, J. Am Chem Soc. 2011;133:3296; h) Barluenga
J, Quiňones N, Cabal M-P, Aznar F, Valdés C, Angew Chem Int
Ed. 2011;50:2350; Angew Chem. 2011;123:2398; i) Zhou L, Ye F,
Ma J, Zhang Y, Wang J, Angew Chem Int Ed. 2011;50:3510;
Angew Chem. 2011;123:3572; j) Chen Z-S, Duan X-H, Wu L-Y,
Ali S, Ji K-G, Zhou P-X, Liu X-Y, Liang YM, Chem Eur J.
2011;17:6918; k) Ye F, Ma X, Xiao Q, Li H, Zhang Y, Wang J, J
Am Chem Soc. 2012;134:5742; l) Yao T, Hirano K, Satoh T,
Miura M, Angew Chem Int Ed. 2012;51:775; Angew Chem.
2012;124:799; m) Xu S, Wu G, Ye F, Wang X, Li H, Zhao X,
Zhang Y, Wang J, Angew Chem Int Ed. 2015;54:4669; Angew
Chem. 2015;127:4752.
The tetraketo compounds are useful intermediate for
heterocycle synthesis. Under mild acidic conditions, tetraketones
undergo
intramolecular
condensation
to
generate
xanthendiones.12 The base free clean condensation of N-
tosylhydrazone with dimedone encouraged us to carry out one-
pot synthesis of xanthendione. Thus, addition of 0.10 equivalent
of p-toluenesulfonic acid to the reaction mixture of N-
tosylhydrazone 1a and dimedone resulted into xanthendione 10a
in 82% yields (Table 3). Similarly, N-tosylhydrazone generated
from 1-naphthaldehyde and pyridine-3-carboxyladehyde also
produced the corresponding xanthenediones 10b and 10c in high
yields under one-pot operation. p-Toluenesulfonic acid must be
added after complete conversion of N-tosylhydrazone to
tetraketone for obtaining high yields of xanthendione.
4. a) Hamze A, Tréguier B, Brion J-D, Alami M, Org Biomol Chem.
2011;9:6200; b) Aziz J, Brion JD, Hamze A, Alami M, Adv Synth
Catal. 2013;355:2417; c) Roche M, Frison G, Brion JD, Provot O,
Hamze A, Alami M. J Org. Chem. 2013;78:8485; d) Roche M,
Bignon J, Brion JD, Hamze A, Alami M,
2014;79:7583.
J Org Chem.
5. For a selected example, see: Barluenga J, Gamasa MT, Aznar F,
Valdés C. Angew Chem Int Ed. 2010;49:4993; Angew Chem.
2010;122:5113.
In summary, transition metal and base free coupling of N-
tosylhydrazones
with
5,5-dimethylcyclohexane-1,3-dione
generates synthetically important tetraketones in high yields.13
Reactivity studies of N-tosylhydrazones derived from aromatic
aldehydes exhibit that the coupling reaction tolerates a methoxy
groups but fails with a hydroxyl group at the ortho position. N-
tosylhydrazone generated from α,β-unsaturated aldehyde
provides Knoevenagel adduct under the base free conditions. The
mild reaction conditions enabled the synthesis of tetraketone
having N-Boc indole moiety in high yields. N-tosylhydrazone can
also be converted to xanthendiones in one-pot operation under
mild acidic conditions in high yields. Initial results suggest that
synthesis of β-keto enol ether is possible under transition metal
free coupling of N-tosylhydrazone with dimedone.
6. For selected examples, see: a) Feng X-W, Wang J, Zhang J, Yang
J, Wang N, Yu X-Q. Org Lett. 2010;12:4408; b) Ding Q, Cao B,
Yuan J, Liu X, Peng Y. Org Biomol Chem. 2011;9:748; c) Lin Y,
Luo P, Zheng Q, Liu Y, Sang X, Ding Q. RSC Adv. 2014;4:
16855; d) Mao S, Gao Y-R, Zhu XQ, Guo D-D, Wang Y-Q. Org
Lett. 2015;17:1692; e) Li L-L, Gao L-X, Han F-S. RSC Adv.
2015;5;29996; f) Tsai AS, Curto JM, Rocke BN, Dechert-Schmitt
AMR, Ingle GK, Mascitti V. Org Lett. 2016;18:508.
7. Sun C.-L., Shi Z.-J. Chem Rev. 2014;114:9219
8. Rao KP, Basak AK, Deb PK, Sharma S, Reddy LKK. Tetrahedron
Lett. 2013;54:3694
9. a) Knoevenagel condensation of 2,4-petanedione with N-
tosylhydrazones using stoichiometric amount of CuCl2 was
reported, see: Attanasi O, Filippone P, Mei A. Synth Commun.
1983;13:1203; b) Intramolecular cyclization of dicarbonyl
compounds via N-tosylhydrazone has been reported, see: Zhu C,
Qiu L, Xu G, Li J, Sun J. Chem Eur J. 2015;21:12871
Acknowledgments
Financial assistance from DST-SERB (YSS/2014/000957) is
gratefully acknowledged. CA thanks UGC for research
fellowship. We thank MNIT Jaipur for NMR spectra.
10. K2CO3 mediated coupling of dimedone with N-tosylhydrazone
Supplimentary data
generated from cyclohexanone in DMF at 110 oC also resulted
Supplementary data is available for the manuscript

4
into O-alkylated dimedone in 23% yields
(see
supporting
information).
11. T.-W. Chung, B.D. Narhe, C.-C. Lin, C.-M. Sun, Org. Lett. 2015,
17, 5368. For details, see supporting information of this
manuscript.
12. For selected recent publications on xanthendiones, see: a)
Sanghanezad SJ, Nazari Y, Davod F. RSC Adv. 2016;6:25525; b)
Das PJ, Das J. RSC Adv. 2015;5:11745; c) Shirini F, Abedini M,
Seddighi M, Jolodar OG, Safarpoor M, Langroodi N, Zamani
S. RSC Adv. 2014;4:63526.
13. Experimental procedure for the synthesis of tetraketone:
A
mixture of N-tosylhydrazone 1a (200 mg, 0.73 mmol), dimedone
o
(214 mg, 1.53 mmol) in toluene (3.0 mL) was stirred at 110 C for
30 min. The reaction mixture was then cooled to rt and diluted
with ethyl acetate (25 mL). The organic layer was washed with
5% AcOH solution (aq) (1 x 10 mL), brine (1 x 10 mL), dried over
Na2SO4 solution and evaporated under reduced pressure. The
crude product was purified by silica gel column chromatography
using 10% ethyl acetate in hexanes as eluent to obtain tetraketo
compound 5a (242 mg, 90%) as a white solid (Please see the
supplementary information for spectral data).

____________________________________________________________________________
Table 1: Optimization of conditions for coupling of N-tosylhydrazone with dimedone
Yield (%)a
Dimedone
Entry
Base (eq)
Conditions
(eq)
3
28
30
26
25
27
26
45
30
trace
-
4
-
5a
15
18
20
16
15
20
34
48
82
85
90b
a
b
c
d
e
f
1.0
1.0
1.0
1.0
1.0
1.0
2.0
2.0
2.0
2.0
2.1
K2CO3 (1.1) DMF, 110 oC, 30 min
Cs2CO3 (1.1) DMF, 110 oC, 30 min
K2CO3 (1.1) DMSO, 110 oC, 45 min
K2CO3 (1.1) DMPU, 110 oC, 30 min
K2CO3 (1.1) NMP, 110 oC, 45 min
K2CO3 (1.1) HMPA, 110 oC, 30 min
K2CO3 (1.1) DMF, 110 oC, 30 min
K2CO3 (1.1) Dioxane, 110 oC, 30 min
K2CO3 (1.1) Toluene, 110 oC, 15 min
K2CO3 (0.5) Toluene, 110 oC, 15 min
-
-
-
g
h
i
14
10
-
j
-
k
-
-
Toluene, 110 oC, 15 min
-
-
aAll reactions were carried out using 1.0 eq of N-tosylhydrazone in appropriate solvent (0.5M)
breaction was carried out in absence of K2CO3

Table 2: Synthesis of tetraketones from N-tosylhydrazonesa
aAll reactions were carried out using 1.0 eq of N-tosylhydrazone, 2.1 eq of dicarbonyl
compound in toluene (0.4 M) at 110 oC; NR = no reaction; ND = yield not determined

Table 3: One-pot synthesis of xanthenedione from N-tosylhydrazone
aTsOH was added after complete conversion of N-tosylhydrazone to tetraketone;
b1.1 eq of TsOH was used and product isolated after neutralization with aq. NaHCO3

8
.
Highlights:
1. Transition metal and base free coupling
2. Tetraketones synthesis under mild
conditions in high yields
3. Wide substrate scope.
4. Base mediated reactions generate C-O
coupling as major product.
5. One-pot synthesis of xanthenedione under
mild acidic conditions.