Ru-Catalyzed One-Pot Diannulation of Heteroaryls: Direct Access to π-Conjugated Polycyclic Amides

Article abstract of DOI:10.1021/acs.orglett.6b03314

A novel Ru-catalyzed oxidative double annulation of heteroarenes with symmetrical and unsymmetrical alkynes is reported. A general method for the unsymmetrical annulation of heteroarenes with two distinct alkynes is showcased for the first time. Methylphenyl sulfoximine (MPS) plays an important role in the annulations of heteroarenes and allows the construction of structurally complex π-conjugated heteroarene-fused polycyclic amide skeletons via the formation of multiple C-C and C-N bonds in a single operation. The reaction exhibits excellent substrate scope and tolerates a wide range of functional groups.

Full text of DOI:10.1021/acs.orglett.6b03314

Letter
pubs.acs.org/OrgLett
Ru-Catalyzed One-Pot Diannulation of Heteroaryls: Direct Access to
π‑Conjugated Polycyclic Amides
Majji Shankar, Koushik Ghosh, Kallol Mukherjee, Raja K. Rit, and Akhila K. Sahoo*
School of Chemistry, University of Hyderabad, Hyderabad-500046, India
S
* Supporting Information
ABSTRACT: A novel Ru-catalyzed oxidative double annulation of heteroarenes with symmetrical and unsymmetrical alkynes is
reported. A general method for the unsymmetrical annulation of heteroarenes with two distinct alkynes is showcased for the first
time. Methylphenyl sulfoximine (MPS) plays an important role in the annulations of heteroarenes and allows the construction of
structurally complex π-conjugated heteroarene-fused polycyclic amide skeletons via the formation of multiple C−C and C−N
bonds in a single operation. The reaction exhibits excellent substrate scope and tolerates a wide range of functional groups.
eteroaryls demonstrate unequivocal importance in chem-
Histry as these moieties are widespread in natural products,
as well as in pharmaceuticals, agrochemicals and organic
materials.1 Notably, π-conjugated polycyclic heteroaryl scaffolds
are invariably found in biologically active molecules;2 on the
other hand, polycyclic heteroarenes significantly contribute to
aggregation-induced emission (AIE) phenomenon, a feature
essential for optoelectronic materials. Hence, the discovery of
novel heteroarene skeletons clearly attracts considerable
attention.3 The π-extended heteroarenes are efficiently formed
by the transition metal (TM)-catalyzed directing group (DG)-
promoted regioselective oxidative annulation of heteroarenes
with alkynes, where ubiquitous C−H bonds systematically
participate in the rapid introduction of complexity and diversity
in a molecule.4−7 Notably, the monoannulation of amide-aided
arenes with alkynes easily fabricates quinolones, while double
annulation efficiently affords unusual π-conjugated polycyclic
fused heteroarenes.3b,8
The double annulation of DG-enabled heteroaryl carboxylic
acid derivatives with unactivated alkynes has rarely been
examined using Rh catalysts.9 It is possible that the “heteroatom
Figure 1. Multiple annulations of (hetero)aryls.
poisoning effect to TM” arguably renders the reaction ineffective.10
Clearly, the use of a Ru catalyst for the direct double annulation
C−C and two C−N) bonds (Figure 1b). Hence, a novel double
annulation of heteroarenes with two different alkynes is reported.
The MPS-DG plays a vital role in the Ru-catalyzed one-pot
diannulations of heteroaryls.
As envisioned, the feasibility of the Ru-catalyzed double
annulation of MPS-coupled 5-methyl-thiophene-2-carboxylate
2a with diphenylacetylene (3a) under the catalytic conditions,
{[RuCl2(p-cymene)]2 (10 mol %), AgSbF6 (40 mol %), and
of DG-molded heteroaryl amides with either symmetrical or
unsymmetrical alkynes has not been explored (Figure 1a). In
addition, the twofold annulation of ortho-substituted DG-
molded arenes with alkynes has been particularly unsatisfac-
tory.11
Despite these inherent challenges, we became interested in
viable synthetic routes and report herein the use of a cost-
effective, air-stable Ru-catalyst for a one-pot double annulation of
MPS-enabled heteroarenes and ortho-substituted arenes with
unactivated alkynes; this process affords complex polyfused π-
extended heterocyclic amides via the formation of four (two
Received: November 4, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03314
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Cu(OAc)2·H2O (1.5 equiv) in 1,4-dioxane at 120 °C for 24 h}
was found to be viable, affording 4a (81%; four-ring-fused
heteroaryl scaffold) [eq 1].12,13 AgSbF6 (40 mol %) is adequate
generating the active catalyst.
reliably building pyrrole, indole, pyrazole, and quinoline fused
polycyclic (four/five-ring-fused) amides 4g−j; thus, the strong
coordination ability of “nitrogen” in N-heteroarenes to TM did
not obstruct the reaction. A complex dibenzo[b,d]furan bearing
4k (51%; six-ring fused) was also synthesized. Annulation of 3-
carboxyl thiophene (2l) or furan (2m) derivatives with 3a
selectively occurred at the C2-position, yielding 4l (55%) and 4m
(78%), respectively. To note, annulation of 2,5-bis-MPS tethered
thiophene derivative 2n occurred on only one side; probably the
steric encumbrance of 4n did not ensue further activation.
We next examined the reactivity of various 1,2-diaryl
acetylenes in this direct double annulation (Scheme 2).
The generality of this Ru-catalyzed double annulation of MPS-
tethered heteroaryls with 3a is detailed in Scheme 1. Thiophene
Scheme 2. Double Annulation of Heteroaryls with 1,2-
Diarylacetylenes
a
Scheme 1. Double Annulation of Heteroaryls with 1,2-
a
Diphenylacetylene
a
Conditions: 2 (0.5 mmol), 3 (1.5 mmol), Ru-catalyst (10 mol %),
AgSbF6 (40 mol %), Cu(OAc)2·H2O (0.75 mmol), 1,4-dioxane (3.0
b
mL) at 120 °C for 24 h. 2b (0.3 mmol) was used.
Gratifyingly, a wide range of alkynes with the substituents in
the arenes [p-electron-donating (tBu), p-halo (F, Cl, or Br), or p-
electron-withdrawing (COMe)] smoothly underwent annula-
tion with 2b to produce 5a−e in excellent yields. Likewise, furan
5f−i and N-methyl pyrrole 5j−k bearing polycyclic amides were
fruitfully prepared. As expected, annulation of 2b with a meta or
meta,para-disubstituted arene bearing alkynes exclusively deliv-
ered 5l−n with the functionalization of the sterically less
crowded C−H bond of arene, albeit in moderate yield.
a
Conditions: 2 (0.5 mmol), 3a (1.5 mmol), Ru-catalyst (10 mol %),
AgSbF6 (40 mol %), Cu(OAc)2·H2O (0.75 mmol), 1,4-dioxane (3.0
mL) at 120 °C for 24 h. 2k (0.3 mmol) was used.
b
The manufacture of a large variation of novel π-extended four/
five/six-ring-fused heteroaryl scaffolds from MPS-tether hetero-
aryl carboxylic acid derivatives (Scheme 1 and 2), which is
otherwise difficult to access, truly validates the synthetic
versatility of the challenging direct double-annulation of the
heteroarene core under the Ru-catalysis. This result significantly
encouraged envisaging a double unsymmetrical annulation of 2
and benzothiophene derivatives 2b−d were reacted efficiently,
accessing 4b−d in good to excellent yields. X-ray analysis
unambiguously elucidated the structure of 4b.14 Likewise, the
oxygen bearing heteroarenes, furan (4e, 85%) and benzofuran
(4f, 89%), were readily synthesized. To our delight, the
annulations were successfully exhibited with N-heteroarenes,
B
DOI: 10.1021/acs.orglett.6b03314
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Letter
a
with two distinct unactivated alkynes (Scheme 3). To our
satisfaction, the reaction of 2b with 3a under the Ru−Ag catalysis
Scheme 4. Double Annulation of o/m-Substituted Arenes
Scheme 3. Sequential and One-Pot Double Annulation of
a
Heteroaryls with Different Alkynes
a
Conditions: 8 (0.5 mmol), 3a (1.5 mmol), Ru-catalyst (10 mol %),
AgSbF6 (40 mol %), Cu(OAc)2·H2O (0.75 mmol) in 1,4-dioxane (3.0
mL) at 120 °C for 24 h.
a
Conditions: 2b (0.5 mmol), 3 (0.75 mmol), Ru-catalyst (5.0 mol %),
AgSbF6 (20 mol %), AcOH (1.5 equiv), 1,2-DCE (2.5 mL) at 120 °C
for 20 h. 6 (0.25 mmol), 3 (0.375 mmol), Ru-catalyst (5.0 mol %),
AgSbF6 (20 mol %), Cu(OAc)2·H2O (1.5 equiv), 1,4-dioxane (2.0
mL) at 120 °C for 20 h. 2b + 3a under 1,4-dioxane at 60 °C, 11 h,
then 3b was added and heated at 120 °C for 11 h.12
in the presence of AcOH led primarily to the monoannulation
product 6a (64%);7j,k subsequent annulation with 4-octyne (3b)
in Ru−Ag catalysts and Cu(OAc)2·H2O in 1,4-dioxane
successfully delivered the unsymmetrical double annulation
product 7a (65%) (Scheme 3). Likewise, the products with the
fusion of different 1,2-diaryl acetylenes [aryl-heteroaryl (7b)]
and [aryl(electron-rich)-aryl(electron-poor) (7c)] were con-
structed in appreciable yields.15 Interestingly, one-pot unsym-
metrical double annulations of 2b with 3a and 4-octyne (3b)
provided 7a in 51% yield. The current unsymmetrical
functionalization of multiple C−H bonds, centered on
heteroarenes, is a distinct advantage over the complementary
methods.3b,8,12
Of note, the DG-assisted direct double annulations of ortho-
substituted arenes suffer mostly with poor performance.11
Pleasingly, the direct double annulations of o-F/OPh/Me
substituted N-aroyl sulfoximine derivatives 8 with 3a under the
optimized conditions resulted 9a (82%), 9b (70%), and 9c
(60%) (Scheme 4). A regioselective annulation at the sterically
less hindered o-C−H bond exclusively occurred with m-CF3
bearing an arene to yield 9d.
Exploration to achieve the double annulation of 2b with 4-
octyne (3b) led exclusively to monocyclized product 10; further
annulation by activating the C(sp3)−H bond turned futile [eq 2].
Interestingly, formation of 11a (56%) and 11b (14%) from 2b
and methyl phenylacetylene (3c) suggested that the mono-
cyclization product with the methyl group adjacent to the thionyl
moiety was attained in situ, which subsequently participated in
the second cyclization [eq 3]. A large scale synthesis of 4b (1.38
g) ascertained the robustness of the catalytic system. The
recovery of methylphenyl sulfoxide (12), the precursor for MPS,
makes this transformation practical [eq 4],16 advocating the
transformable nature of the MPS moiety.
Although the mechanistic details are yet to be established, the
reaction possibly initiates with the coordination of MPS to the
active catalyst, generated from [{RuCl2(p-cymene)}2], AgSbF6,
and Cu(OAc)2, and activates the ortho C−H bond of
heteroarenes.12 Next, the interaction of alkyne to the cyclo-
metalated complex followed by the insertion delivers mono-
annulation product and 12. Next, the second annulation of the
monocyclized product finally provides the desired polycyclic
fused heterocycles.8,12 The exact role of Cu(OAc)2 is not clear;
however, the results in Scheme 3 suggest that it helps in the
generation of the active catalyst and behaves as an oxidant in the
second annulation.
To understand the importance of the novel π-conjugated
heteroarene-fused polycyclic amides, the steady state absorption
and photoluminescence (PL) measurements were executed for
4j and 4k in acetone (Figure 2). Absorbance at 416 and 457 nm
with broad PL in the visible range has clearly been observed. The
presence of large π-conjugation in these molecules unequivocally
tunes the PL band. We believe these compounds, by virtue of
their absorbance and fluorescence properties, will find use as
fluorescent labels to act as reporter groups in macromolecular
studies.17
C
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(5) Selected Rh- and Ru-catalyzed oxidative annulation reviews:
(a) Satoh, T.; Miura, M. Chem. - Eur. J. 2010, 16, 11212. (b) Wencel-
Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011, 40, 4740.
̈
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Mascarenas, J. L. Angew. Chem., Int. Ed. 2016, 55, 11000.
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(6) Selected examples of Rh-catalyzed annulation: (a) Fukutani, T.;
Umeda, N.; Hirano, K.; Satoh, T.; Miura, M. Chem. Commun. 2009,
5141. (b) Too, P. C.; Wang, Y. F.; Chiba, S. Org. Lett. 2010, 12, 5688.
(c) Su, Y.; Zhao, M.; Han, K.; Song, G.; Li, X. Org. Lett. 2010, 12, 5462.
(d) Morimoto, K.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2010, 12,
2068. (e) Guimond, N.; Gouliaras, C.; Fagnou, K. J. Am. Chem. Soc.
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L.; Ju, J.; Bin, Y.; Hua, R. J. Org. Chem. 2012, 77, 5794. (k) Dong, W.;
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2013, 52, 11573. (l) Cheng, Y.; Bolm, C. Angew. Chem., Int. Ed. 2015, 54,
12349.
(7) Selected examples of Ru-catalyzed annulation: (a) Ackermann, L.;
Lygin, A. V.; Hofmann, N. Angew. Chem., Int. Ed. 2011, 50, 6379. (b) Li,
B.; Feng, H.; Xu, S.; Wang, B. Chem. - Eur. J. 2011, 17, 12573.
(c) Ackermann, L.; Fenner, S. Org. Lett. 2011, 13, 6548. (d) Ackermann,
L.; Pospech, J.; Graczyk, K.; Rauch, K. Org. Lett. 2012, 14, 930.
(e) Parthasarathy, K.; Senthilkumar, N.; Jayakumar, J.; Cheng, J. C.-H.
Org. Lett. 2012, 14, 3478. (f) Chinnagolla, R. K.; Pimparkar, S.;
Jeganmohan, M. Org. Lett. 2012, 14, 3032. (g) Reddy, M. C.;
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R.; Rit, R. K.; Shankar, M.; Sahoo, A. K. J. Org. Chem. 2014, 79, 6123.
(k) Ghosh, K.; Rit, R. K.; Ramesh, E.; Sahoo, A. K. Angew. Chem., Int. Ed.
2016, 55, 7821.
Figure 2. Normalized absorption and PL spectra of derivatives of 4j, 4k
dispersed in acetone (1 × 10−5 M) and photographs of derivatives of 4j,
4k in acetone under the UV lamp.
In summary, a notable Ru(II)-catalyzed oxidative double
annulation of MPS-DG-enabled heteroarenes with unactivated
alkynes involving one-pot twofold C−H activation is reported.
The developed method affords complex heteroarene-fused
polycyclic amides via the construction of four bonds (two
C−C and two C−N) in a single operation. In addition, excellent
substrate scope and functional group tolerance are observed. The
unprecedented unsymmetrical double annulation of heteroar-
enes with two distinct alkynes is successfully demonstrated. The
steady state absorption and photoluminescence (PL) measure-
ment of compounds is revealed.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b03314.
Detailed experimental procedures, NMR spectra (PDF)
HRMS data (PDF)
X-ray crystallographic data (CIF, CIF)
(8) (a) Li, B.; Feng, H.; Wang, N.; Ma, J.; Song, H.; Xu, S.; Wang, B.
Chem. - Eur. J. 2012, 18, 12873. (b) Wang, N.; Li, B.; Song, H.; Xu, S.;
Wang, B. Chem. - Eur. J. 2013, 19, 358.
AUTHOR INFORMATION
Corresponding Author
■
(9) (a) Song, G.; Chen, D.; Pan, C.-L.; Crabtree, R. H.; Li, X. J. Org.
Chem. 2010, 75, 7487. (b) Mochida, S.; Umeda, N.; Hirano, K.; Satoh,
T.; Miura, M. Chem. Lett. 2010, 39, 744. (c) Jayakumar, J.; Parthasarathy,
J. K.; Chen, Y.-H.; Lee, T.-H.; Chuang, S.-C.; Cheng, C.-H. Angew.
Chem., Int. Ed. 2014, 53, 9889. (d) Yu, D.-G.; de Azambuja, F.; Gensch,
T.; Daniliuc, C. G.; Glorius, F. Angew. Chem., Int. Ed. 2014, 53, 9650.
(e) Su, B.; Wei, J.-B.; Wu, W.-L.; Shi, Z.-J. ChemCatChem 2015, 7, 2986.
(f) Ge, Q.; Hu, Y.; Li, B.; Wang, B. Org. Lett. 2016, 18, 2483. (g) Peng, S.;
Liu, S.; Zhang, S.; Cao, S.; Sun, J. Org. Lett. 2015, 17, 5032.
(10) (a) Shang, M.; Sun, S.-Z.; Dai, H.-X.; Yu, J.-Q. J. Am. Chem. Soc.
2014, 136, 3354. (b) Lu, Y.; Wang, H.-W.; Spangler, J. E.; Chen, K.; Cui,
P.-P.; Zhao, Y.; Sun, W.-Y.; Yu, J.-Q. Chem. Sci. 2015, 6, 1923.
(11) Lin, H.; Li, S.-S.; Dong, L. Org. Biomol. Chem. 2015, 13, 11228.
(12) See the Supporting Information.
*E-mail: akhilchemistry12@gmail.com; akssc@uohyd.ac.in.
ORCID
Akhila K. Sahoo: 0000-0001-5570-4759
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by CSIR (02/(0155)/13/EMR-II).
M.S., K.G., K.M., and R.K.R. thank CSIR, India, for a fellowship.
We thank Navendu Mondal and Mou Mandal (University of
Hyderabad) for fluorescence measurement and helpful dis-
cussions.
(13) Amide assisted direct double annulations of benzamide with
diphenyl acetylene under the optimized conditions provided 24% of the
desired product.
(14) CCDC 1506280 [4b] and 1506279 [9a] contain the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
(15) The Ru-catalyzed annulation of quinolone with alkynes is
difficult; presumably the MePhSO has no role in the reaction
outcome.
(16) Yadav, M. R.; Rit, R. K.; Sahoo, A. K. Chem. - Eur. J. 2012, 18,
5541.
(17) Liu, B.; Chen, X.; Zou, Y.; Xiao, L.; Xu, X.; He, Y.; Li, L.; Li, Y.
Macromolecules 2012, 45, 6898.
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