Expedient synthesis of new cinnoline diones by Ru-catalyzed regioselective unexpected deoxygenation-oxidative annulation of propargyl alcohols with phthalazinones and pyridazinones

Article abstract of DOI:10.1039/c5cc09347c

Ruthenium-catalyzed simple, cascade and one-pot synthesis of cinnoline-fused diones has been carried out by the C-H activation of phthalazinones/pyridazinones accomplished by the unusual deoxygenation of propargyl alcohols. The bond selectivity is accredited to the traceless directing nature of the hydroxyl group of propargyl alcohol. A sequential C-H activation, insertion and deoxy-oxidative annulation has been proposed based on the preliminary mechanistic study.

Full text of DOI:10.1039/c5cc09347c

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DOI: 10.1039/C5CC09347C
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Expedient Synthesis of New Cinnolinediones by Ru-Catalyzed
Regioselective Unexpected Deoxygenation-Oxidative Annulation
of Propargyl Alcohols with Phthalozinones and Pyridizinones
Received 00th January 20xx,
Accepted 00th January 20xx
Subramani Rajkumar,a S. Antony Savarimuthu,b Rajendran Senthil Kumaran,c C. M. Nagarajad and
Thirumanavelan Gandhi*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
Ruthenium catalyzed simple, cascade and one-pot synthesis of
cinnoline-fused diones has been synthesized by the C–H activation
of phthalozinones/pyridizinones complied by the unusual
deoxygenation of propargyl alcohols. The bound selectivity is
accredited to the traceless directing nature of hydroxyl group of
propargyl alcohol. A sequential C−H acꢀvaꢀon, inserꢀon and
deoxy-oxidative annulation has been proposed based on the
preliminary mechanistic study.
Transition-metal-catalyzed direct C-H bond functionalization has
taken a centre stage in modern organic synthesis as it could usher
the chemists for rapid construction of complex compounds from
easily accessible substrates.1 Embracing this strategy, various fused
polyheterocycles has been generated exhibiting step- and atom-
economy, high selectivity and efficiency overcoming the traditional
pre-functionalization route.2 In addition, tethering the appropriate
directing group (DG) in the substrate which can direct a metal
catalyst to the reactive centre enables the diverse C-H bond
functionalization.3 In this regard, oxidative annulation reaction
using alkynes are among the most acclaimed and well-studied
approaches of C-C and C-N/C-O bond formation.3d, Specifically,
4
bond formation using 1-arylhydrazine-1,2-dicarboxylate and aryl
iodide as the precursors.10
syntheses of cinnolines and their derivatives are privileged
polyheterocyclic scaffolds prevalent in natural products and are
known for exhibiting interesting pharmaceutical5 and optical
properties.6 Recently, Zhang, Cheng, You and Lee have disclosed the
Herein, we wish to report
a
less expensive Ru-catalyzed
of easily accessible
oxidative annulation reaction
phthalazinone/pyridizinone with propargyl alcohol to afford
cinnoline-fused diones in moderate to excellent yields. Besides, we
witnessed unprecedented deoxygenation of propargyl alcohol
which is considered as a poor leaving group (Figure 1a).11 It is quite
well-known that deoxygenation of alcohols to alkanes is very
attractive process as it holds good scope in converting the natural
products to biofuels. However, the removal of a hydroxyl group to
form corresponding alkanes is very challenging, and it is achieved by
classical Barton-McCombie reaction or by other multistep
processes.12 Initially, 2-phenyl-2,3-dihydrophthalazine-1,4-dione 1a
was treated with 3-phenylprop-2-yn-1-ol 2a in the presence of
[RuCl2(p-cymene)]2) (5 mol %), and NaOAc (30 mol %) in methanol
at 80 °C for 22 h. To our surprise, we observed the cascade reaction
involving facile deoxy-oxidative annulation reaction resulting in the
formation of 3aa, but in poor yield. However, it is a noteworthy
transformation signifies the concomitant regioselectivity and
deoxygenation process (Figure 1b).
construction
of
cinnolines
through
Rh-catalyzed
C-H
activation/cyclization of azobenzene or N-aryl-1H-pyrazol-5(4H)-one
with simple alkynes or Meldrum’s acid by employing nitrogen as a
directing group.7 In addition, Ge and coworkers have developed
intramolecular dehydrogenative cyclization of N-methyl-N-
phenylhydrazones to yield 3-aryl-substituted cinnolines.8
Simultaneously, Willis et al reported the copper-catalyzed
annulation of
a simple hydrazine diester with various 2-(2-
bromoalkenyl)aryl bromides to give functionalized cinnolines.9 Very
recently, Subba Reddy and coworkers showed Pd-catalyzed
synthesis of cinnoline derivatives involving sequential C-C and C-N
aMaterials Chemistry Division, School of Advanced Sciences, VIT University, Tamil Nadu
632014 ( India) Email: velan.g@vit.ac.in
bDepartment of Chemistry, St. Xavier’s College, Palayamkottai, Tamil Nadu 627002
(India)
cSyngene International Limited, Biocon, Bangalore, 560099 (India)
dDepartment of Chemistry, Indian Institute of Technology Ropar, Punjab 140001 (India)
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Scheme 5 Proposed mechanism for deoxy-oxidative annulation
40, 1885; f) D. A. Colby, R. G. Bergman and J. A. Ellman, Chem. Rev., 2010, 110
,
624; g) T. W. Lyons and M. S. Sanford, Chem. Rev., 2010, 110, 1147; h) G. Song,
F. Wang and X. Li, Chem. Soc. Rev., 2012, 41, 3651; i) J. Wencel-Delord, T.
Droge, F. Liu and F. Glorius, Chem. Soc. Rev., 2011, 40, 4740; j) K. Fagnou, Top.
Curr. Chem., 2010, 292, 35; k) J.-Q. Yu and Z. Shi, C-H Activation, Springer,
Berlin, 2010.
O
O
N
N
HN
N
O
O
2
3
2. a) P. A. Wender, V. A. Verma, T. J. Paxton and T. H. Pillow, Acc. Chem.
Res., 2008, 41, 40; b) B. Trost, Science, 1991, 254, 1471.
O
II
Ru
A
O
O
O
2 Cu(OAc)
2 Cu(OAc)2
3. a) C.-Z. Luo, P. Gandeepan and C.-H. Cheng, Chem. Commun., 2013, 49
,
II
Ru
O
8528; b) J. Dong, Z. Long, F. Song, N. Wu, Q. Guo, J. Lan and J. You, Angew.
Chem., Int. Ed., 2013, 52, 580; c) C. Wang and Y. Huang, Synlett, 2013, 24, 145;
d) L. Ackermann, Acc. Chem. Res., 2014, 47, 281; e) S. Rajkumar, S. Karthik and
T. Gandhi, J. Org. Chem., 2015, 80, 5532; f) S. Bag, T. Patra, A. Modak, A. Deb,
S. Maity, U. Dutta, A. Dey, R. Kancherla, A. Maji, A. Hazra, M. Bera and D.
Maiti, J. Am. Chem. Soc., 2015, 137, 11888; g) A. Deb, S. Bag, R. Kancherla and
D. Maiti, J. Am. Chem. Soc., 2014, 136, 13602; h) M. Bera, A. Maji, S. K. Sahoo
and D. Maiti, Angew. Chem., Int. Ed., 2015, 54, 8515.
N
O
N
RuII
[RuCl2(p-Cymene)]2
O
O
+
N
F
O
OAc-
N
O
O
2
AcOH
B
O
O
O
O
N
II
Ru
4
5
4. a) T. Aggarwal, R. R. Jha, R. K. Tiwari, S. Kumar, S. K. R. Kotla, S. Kumar and
A. K. Verma, Org. Lett., 2012, 14, 5184; b) C. Kornhaaß, J. Li and L. Ackermann,
J. Org. Chem., 2012, 77, 9190; c) L. Ackermann and A. V. Lygin, Org. Lett.,
2012, 14, 764; d) L. Ackermann, A. V. Lygin and N. Hofmann, Angew. Chem.,
Int. Ed., 2011, 50, 6379.
H
N
2 Cu(OAc)
2 Cu(OAc)2
O
O
O
6ea
RuII
O
HN
N
O
N
N
O
O
O
O
E
5. a) W. Lewgowd and A. Stanczak, Arch. Pharm. Chem. Life Sci., 2007, 340
65; b) E. M. Lourie, J. S. Morley, J. C. E. Simpson and J. M. Walker, Br. J.
Pharmacol. Chemother., 1951, , 643; c) Y. Yu, S. K. Singh, A. Liu, T.-K. Li, L. F.
,
6
Liu and E. J. LaVoie, Bioorg. Med. Chem., 2003, 11, 1475; d) P. Barraja, P.
Diana, A. Lauria, A. Passannanti, A. M. Almerico, C. Minnei, S. Longu, D.
RuII
II
Ru
O
O
O
N
Congiu, C. Musiu and P. La Colla, Bioorg. Med. Chem. , 1999, 7, 1591; e) N.
Gautam and O. P. Chourasia, Indian J. Chem. Sect. B, 2010, 49, 830; f) P.
Parasuraman, R. S. Shanmugarajan, T. Aravazhi, K. Nehru, T. Mathiazhagan
O
O
O
N
HN
N
O
D
H
C
O
and R. Rajakumari, Int. J. Pharm. Life Sci. , 2012,
6. a) H. Tsuji, Y. Yokoi, Y. Sato, H. Tanaka and E. Nakamura, Chem. -Asian J.,
2011, , 2005; b) X. Shao, X. Luo, X. Hu and K. Wu, J. Phys. Chem. B, 2006, 110
15393; c) J.-C. Chen, H.-C. Wu, C.-J. Chiang, T. Chen and L. Xing, J. Mater.
Chem. C, 2014, , 4835; d) V. Gautheron Chapoulaud, N. Plé, A. Turck and G.
3, 1430.
6
7
To further corroborate this process, in
a
separate reaction
6
,
propargylic ester was chosen as the alkyne source and it was found
out that it undergoes deoxy-oxidative annulation at ease (see
Supplementary Information). Based on the above-mentioned
2
Quéguiner, Tetrahedron, 2000, 56, 5499.
7. a) L. Xing, Z. Fan, C. Hou, G. Yong and A. Zhang, Adv. Synth. Catal., 2014,
356, 972; b) K. Muralirajan and C.-H. Cheng, Chem. - Eur. J., 2013, 19, 6198; c)
experimental results,
a plausible mechanism was outlined in
D. Zhao, Q. Wu, X. Huang, F. Song, T. Lv and J. You, Chem. -Eur. J., 2013, 19
6239; d) J.-Y. Son, S. Kim, W. H. Jeon and P. H. Lee, Org. Lett., 2015, 17, 2518.
8. G. Zhang, J. Miao, Y. Zhao and H. Ge, Angew. Chem., Int. Ed., 2012, 51
8318.
9. C. J. Ball, J. Gilmore and M. C. Willis, Angew. Chem., Int. Ed., 2012, 51
5718.
,
,
,
Scheme 5. Initially Ru(II)-catalyzed C-H activation takes place to
give ruthenacycle B, which is followed by the regioselective
insertion of alkyne (in situ formed propargylic ester) gives seven
member Ru(II) species C, which upon isomerise to generate another
intermediate D, in the presence of acidic condition. Further, D was
rearranged to new Ru(II) species E - a γ-deoxygenation step.12d, 14 In
the penultimate step, again seven membered Ru(II) species F is
formed with the removal of -OAc and eventually oxidative
annulated product was generated.
In summary, we have developed a convenient synthesis of new
cinnoline fused-diones by Ru(II)-catalyzed regioselective
deoxygenation-oxidative annulation of propargyl alcohols with
phthalozinones and pyridizinones. This cascade reaction proceeds
8
9
10 10. B. V. S. Reddy, C. R. Reddy, M. R. Reddy, S. Yarlagadda and B. Sridhar,
Org. Lett., 2015, 17, 3730.
11 11. a) R. Zeng and G. Dong, J. Am. Chem. Soc., 2015, 137, 1408; b) L. Qiu, D.
Huang, G. Xu, Z. Dai and J. Sun, Org. Lett., 2015, 17, 1810; c) R. K. Chinnagolla,
S. Pimparkar and M. Jeganmohan, Org. Lett., 2012, 14, 3032; d) S. Gupta, J.
Han, Y. Kim, S. W. Lee, Y. H. Rhee and J. Park, J. Org. Chem., 2014, 79, 9094; e)
A. Seoane, N. Casanova, N. Quiñones, J. L. Mascareñas and M. Gulías, J. Am.
Chem. Soc., 2014, 136, 834; f) N. Guimond, S. I. Gorelsky and K. Fagnou, J. Am.
Chem. Soc., 2011, 133, 6449.
12 12. a) J. M. Herrmann and B. König, Eur. J. Org. Chem., 2013, 2013, 7017; b)
M. Egi, T. Kawai, M. Umemura and S. Akai, J. Org. Chem., 2012, 77, 7092; c) Y.
Nishibayashi, A. Shinoda, Y. Miyake, H. Matsuzawa and M. Sato, Angew.
Chem., Int. Ed., 2006, 45, 4835; d) T. Tsuchimoto, H. Matsubayashi, M. Kaneko,
Y. Nagase, T. Miyamura and E. Shirakawa, J. Am. Chem. Soc., 2008, 130, 15823.
13 13. a) B. Li, H. Feng, N. Wang, J. Ma, H. Song, S. Xu and B. Wang, Chem. -Eur.
J., 2012, 18, 12873; b) L. Ackermann, R. Vicente, H. K. Potukuchi and V.
with the generation of -OAc as the sole by-product.
Broad
substrate scope and excellent functional group tolerance are
highlight of this work. Resultant deoxygenated products could be
impetus to study the detailed mechanism of this process and above
all it opens up new strategy to generate new heterocycles
possessing potential biological and photochemical applications.
Pirovano, Org. Lett., 2010, 12
Macgregor, K. Singh and B. Villa-Marcos, Chem. Sci., 2014,
,
5032; c) K. J. T. Carr, D. L. Davies, S. A.
, 2340.
5
14 14. a) Y. Suzuki, B. Sun, K. Sakata, T. Yoshino, S. Matsunaga and M. Kanai,
Angew. Chem., Int. Ed., 2015, 54, 9944; b) H. Wang, N. Schröder and F. Glorius,
Angew. Chem., Int. Ed., 2013, 52, 5386; c) C. Feng, D. Feng and T.-P. Loh,
Chem. Commun., 2015, 51, 342; d) H. Wang, B. Beiring, D.-G. Yu, K. D. Collins
and F. Glorius, Angew. Chem., Int. Ed., 2013, 52, 12430; e) R. Manikandan, P.
Madasamy and M. Jeganmohan, Chem. -Eur. J., 2015, 21, 13934.
Acknowledgements
This activity is supported by DST (SR/FT/CS-135/2011) and VIT
University, Vellore. Instrumental facility provided by VIT-SIF
gratefully acknowledged. S.R. sincerely thanks DST and CSIR (SRF)
for the fellowships.
15
16
Notes and references
1
1. a) J. Yamaguchi, A. D. Yamaguchi and K. Itami, Angew. Chem., Int. Ed.,
2012, 51, 8960; b) N. Kuhl, M. N. Hopkinson, J. Wencel-Delord and F. Glorius,
Angew. Chem., Int. Ed., 2012, 51, 10236; c) L. Ackermann, Chem. Rev., 2011,
111, 1315; d) P. B. Arockiam, C. Bruneau and P. H. Dixneuf, Chem. Rev., 2012,
112, 5879; e) L. McMurray, F. O'Hara and M. J. Gaunt, Chem. Soc. Rev., 2011,
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