Cyclopenta[b]annulation of Heteroarenes by Organocatalytic γ′[C(sp3)?H] Functionalization of Ynones

Article abstract of DOI:10.1002/chem.201604562

A new approach for the cyclopenta[b]annulation of heteroarenes through metal-free and directing-group-free γ′[C(sp³)?H] functionalization and intramolecular hydroalkylation of ynones has been developed. In an unprecedented event, nucleophilic addition of an organophosphine to the designed ynones triggers γ′[C(sp³)?H] functionalization, leading to the formation of heteroaryl-based ortho-quinodimethane (oQDM) intermediates that undergo carbocyclization to provide cyclopentannulated heteroarenes in good yields and excellent stereoselectivities. Deuterium-labeling experiments substantiated the proposed reaction mechanism as well as the speculated epimerization.

Full text of DOI:10.1002/chem.201604562

A Journal of
Accepted Article
Title: Cyclopenta[b]annulation of Heteroarenes via Organocatalytic
γ'[C(sp3)-H] Functionalization of Ynones
Authors: S. S. V. Ramasastry, Raghu Moluguri, and Jagdeep Grover
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To be cited as: Chem. Eur. J. 10.1002/chem.201604562
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Cyclopenta[b]annulation of Heteroarenes via Organocatalytic
γ’[C(sp3)-H] Functionalization of Ynones
Moluguri Raghu,‡ Jagdeep Grover,‡ and S. S. V. Ramasastry*
Abstract:
A new approach for the cyclopenta[b]annulation of
heteroarenes via metal-free and directing group-free γ’[C(sp3)-H]
functionalization and intramolecular hydroalkylation of ynones has
been developed. In an unprecedented event, nucleophilic addition of
an organophosphine to the designed ynones triggers γ’[C(sp3)-H]
functionalization, leading to the formation of heteroaryl-based ortho-
quinodimethane
(oQDM)
intermediates,
which
undergo
carbocyclization to provide cyclopentannulated heteroarenes in good
yields and excellent stereoselectivities. Deuterium labelling
experiments substantiated the proposed reaction mechanism as well
as the speculated epimerization.
Nucleophilic phosphine catalysis has emerged as a powerful
synthetic tool to rapidly assemble complex carbo- and
heterocyclic structures.[1] Organophosphine catalyzed [C(sp3)-
H]-functionalization of ynones has been the subject of intense
research.[2] In this direction, Tomita,[3] Fu[4] and Ramachary[5]
recently reported inter- and intramolecular phosphine-promoted
approaches for the synthesis of cyclopentanes via α’[C(sp3)-H]-
functionalization of ynones, Scheme 1a. However, to the best of
our knowledge, no attempt for the organocatalytic γ’[C(sp3)-H]-
functionalization of ynones is reported thus far. Herein, we
present
an
unprecedented
γ’[C(sp3)-H]-functionalization
triggered by an organophosphine for the synthesis of a broad
range of cyclopentannulated heteroarenes, Scheme 1a.
In an effort to expand our studies on the organophosphine-
catalyzed cyclopentannulations,[6] we envisioned that the
zwitterionic intermediate B could be generated by the conjugate
Scheme 1.
A
comparison between our design and the existing
organophosphine-catalyzed approaches for the synthesis of cyclopentanes.
addition of
a phosphine to the ynone A, Scheme 1b.
Intramolecular 1,5-proton migration from the ideally situated
benzylic C(sp3)-H could furnish heteroaryl-based ortho-
quinodimethane (oQDM) C. In this context, it is worth mentioning
the existing metal-free approaches developed by Melchiorre
(trienamine-mediated organocatalysis),[7] Chi (N-heterocyclic
carbene catalysis),[8] and Zhang[9] for the generation of
heteroaryl-based oQDMs.[10] The underlying concept in these
studies is that the in situ generated oQDM intermediates
Cyclopenta[b]annulated heteroarenes are especially
attractive due to their widespread occurrence in several
bioactive natural products and pharmaceutically important
compounds.[11] Significantly, the conversion of A to F also
establishes a new variation in the intramolecular hydroalkylation
of ynones. Inter- and intramolecular hydroalkylation of alkenes
and alkynes is well-explored.[12] However, to the best of our
knowledge,
organocatalyzed
intramolecular
(annulative)
undergo
a
typical [4+2]-cycloaddition reaction to afford
hydroalkylation of ynones is not known till date.
heteroarenes annulated with six-membered rings. In contrast,
we propose herein an intramolecular cyclization of the oQDM C
to furnish the ylide D and subsequent 1,2-proton shift followed
by the elimination (regeneration) of phosphine to produce
cyclopenta-fused heteroarenes of the type F.
In order to validate the mechanistic hypothesis presented
in Scheme 1b, we have chosen the ynone 1a as the model
substrate.[13] Various phosphine and solvent combinations were
investigated, and the results are summarized in Table 1.
At the outset, the reaction of 1a was performed with a
catalytic amount of PPh3 in toluene at ambient temperature; this
process yielded no detectable amount of the desired product
even after three days (Table 1, entry 1). On the other hand,
reaction in the presence of PPh2Et, even at elevated temperature
provided only traces of product (Table 1, entry 2). However, to
our delight, PPhMe2 and PMe3-promoted reactions under
ambient conditions furnished the desired product 2a in 67% and
80% yields, respectively (Table 1, entry 3 and 4). The molecular
structure of 2a along with the predicted (E)-geometry across the
olefin were unambiguously confirmed by single crystal X-ray
diffraction analysis.[14]
[*]
M. Raghu, Dr. J. Grover and Prof. Dr. S. S. V. Ramasastry
Organic Synthesis and Catalysis Lab, Department of Chemical
Sciences, Indian Institute of Science Education and Research
(IISER) Mohali, Sector 81, Manuali PO, S. A. S. Nagar, Punjab
140306, India.
E-mail: ramsastry@iisermohali.ac.in (or) ramsastrys@gmail.com
Homepage: http://14.139.227.202/faculty/sastry/
These authors contributed equally to this work.
[‡]
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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Table 1. Optimization of the reaction parameters.[a]
Table 2. Scope of ynones appended to 2-methyl heteroarenes.[a, b, c]
Yield [%][b]
Entry
Catalyst [20 mol %]
Solvent
Time [h]
(E/Z)[c]
PPh3
Toluene
Toluene
Toluene
Toluene
Toluene
ClCH2CH2Cl
THF
72
48
4
-
1
2[d]
PPh2Et
PPhMe2
PMe3
PCy3
<5 (-)
67 (-)
3
0.5
3.5
3
80 (93:7)
90 (88:12)
77 (90:10)
80 (97:3)
-
4
5
PCy3
6
PCy3
4
7
PCy3
MeOtBu
72
3.5
8
9[e]
PCy3
CH2Cl2
93 (98:2)
[a] See the Supporting Information for details of the reaction conditions. [b]
Isolated yields after column chromatography. [c] E/Z ratios were determined
by 1H-NMR analysis. [d] At 80 oC. [e] 10 mol % of the catalyst was employed.
Product 2a was obtained in excellent yield when the
reaction was performed with PCy3 as the catalyst (Table 1, entry
5). Subsequent evaluation of the reaction conditions identified
that 10 mol % PCy3 in DCM was optimal for the transformation
of 1a to 2a (Table 1, entry 9).
The optimized conditions were then applied to various
substrates featuring electronically diverse substituents, Table 2.
During an initial evaluation, a noteworthy role of N-substituents
was realized; electron-withdrawing groups such as Boc or Cbz
favoured the product formation while electron-donating groups
(e.g., Me) failed to promote the reaction (Table 2, 2b-2d). Since
the ynone with N-tosylindole backbone (1a) afforded the best
yield in short turnaround time, subsequent substrate scope was
investigated with N-tosylated indoles. The presence of electron-
donating (-OMe) as well as electron-withdrawing groups (-OTs, -
Cl) on the indole backbone displayed only marginal influence on
the outcome of the reaction (Table 2, 2e-2g). Isolation of
cyclopenta[b]indoles 2h-2l in consistent yields and significant
stereoselectivities indicate the least dependence of this method
on the nature of the substituents on the ynone portion.
[a] See the Supporting Information for details of the reaction conditions. [b]
Isolated yields after column chromatography. [c] E/Z ratios were determined
by 1H-NMR analysis. [d] Yield based on starting material recovery.
With this success, we moved on to exploring the effect of
γ’-branching on the annulation process, Table 3. We envisaged
few advantages of introducing substitution at the γ’-position, (i) it
enables us to assess the impact of diverse substituents on the
acidity of the benzylic C-H, (ii) it generates a new stereogenic
centre in the product and thus provides an opportunity to
develop an enantioselective variant, and (iii) it can significantly
enhance the scope of the reaction.
Generality of the reaction was further verified with
benzothiophene and benzofuran backbones (Table 2). Indeed,
ynones appended to 2-methyl benzothiophene were found to be
superior substrates under the optimized conditions, affording the
respective cyclopenta[b]benzothiophenes (4a-4d) in good yields
and in excellent stereoselectivities. On the other hand, ynones
tethered to benzofurans provided the expected products (Table
2, 6a-6c) though in marginally less yields but in high levels of E-
selectivity. Thus, initial considerations of the phosphine-
catalyzed γ’[C(sp3)-H]-functionalization and intramolecular
hydroalkylation strategy established a straightforward access to
a broad range of cyclopentannulated indoles, benzothiophenes
and benzofurans, which are otherwise difficult-to-access via
contemporary approaches.
Accordingly, a variety of substituents conferring electronic
as well as steric characters were introduced at the γ’-position,
Table 3. The reaction appeared to be quite general with respect
to the substrate designs tested, providing the respective
pentannulated benzothiophenes in consistent yields and high
stereoselectivities (Table 3, 4e-4n). In particular, ynones
possessing electron-donating groups were well-tolerated under
the optimized conditions (Table 3, 4f, 4h and 4m). Substrates
bearing γ’-alkyl (both linear and branched, 4e-4k) as well as γ’-
aryl groups (4l-4n) turned out to be equally efficient, highlighting
the versatility of this protocol. However, several of our efforts to
generate a quaternary/spiro carbon employing this strategy were
unsuccessful (Table 3, 4o and 4p).
Table 3. Scope of γ’-branched benzo[b]thiophen-3-ynones.[a, b, c]
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occurring during the reaction or after the product formation. We
thus resorted to deuterium labeling experiments to corroborate
this hypothesis. It was also anticipated that the labeling
experiments could provide insights about the reaction
mechanism which was proposed to involve various anionic
intermediates (see Scheme 1b).
Table 4. Synthesis of deuterium-incorporated cyclopenta[b]annulated
heteroarenes[a, b, c]
[a] See the Supporting Information for details of the reaction conditions. [b]
Except 2m, yields reported are based on starting material recovery; see ESI
for actual yields. [c] E/Z ratios and percentage deuterium incorporation were
determined by 1H-NMR analysis.
[a] Unless otherwise specified, reaction conditions described in Table 2 were
followed. [b] Isolated yield after column chromatography. [c] E/Z ratios were
determined by 1H-NMR analysis of the purified sample.
Accordingly, the reaction of 1a with PCy3 in THF-D2O
system was evaluated, Table 4.[15] To our surprise and delight,
the reaction underwent phosphine catalyzed hydroalkylative
cyclization under aqueous conditions to straightaway furnish the
deuterated cyclopenta[b]indole 2m in excellent isotopic purity.
Further substrate screening provided few other deuterated
cyclopentannulated indoles and benzothiophenes (2n, 4q-4s) in
excellent yields and good isotopic purities. In addition to
providing simple, efficient and economic access to valuable
deuterium-labelled heterocycles, this reaction also verified the
feasibility of performing the reaction under aqueous conditions,
which is quite uncommon in phosphine chemistry.[16]
Considering the aforementioned findings, we turned our
attention towards the development of a catalytic enantioselective
version. Accordingly, an extensive screening of a variety of
catalyst designs was undertaken with 3e as the model substrate,
Scheme 2. In light of our previous success with the bifunctional
phosphine 7/hexafluoro-2-propanol (HFIP) combination,[6] we
chose this system in the preliminary evaluation. However, the
reaction of 3e under the prototypical conditions failed to
generate the expected product 4e. Subsequent examination of
several catalyst, additive and solvent combinations although
afforded the desired product 4e, but only in poor
enantioselectivities.[13]
Scheme 2. Efforts towards the development of an enantioselective version.
HFIP= hexafluoro-2-propanol, TFE=2,2,2-trifluoroethanol, TFT=trifluorotoluene.
Scheme 3. Plausible mechanistic pathways leading to the deuterium
incorporation.
Intrigued by the lack of asymmetric induction, we
postulated that it could be an issue with the racemization
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2004, 346, 1035; d) X. Lu, Y. Du, C. Lu, Pure Appl. Chem. 2005, 77,
1985; e) V. Nair, R. S. Menon, A. R. Sreekanth, N. Abhilash, A. T. Biju,
Acc. Chem. Res. 2006, 39, 520; f) L. –W. Ye, J. Zhou, Y. Tang, Chem.
Soc. Rev. 2008, 37, 1140; g) S. S. Kinderman, J. H. van Maarseveen,
H. Hiemstra, Synlett 2011, 1693; h) Y. Xiao, Z. Sun, H. Guo, O. Kwon,
Beilstein J. Org. Chem. 2014, 10, 2089; i) T. Wang, X. Han, F. Zhong,
W. Yao, Y. Lu, Acc. Chem. Res. 2016, 49, 1369.
Deuterium incorporation at the β-position can be explained
as in part-a, Scheme 3.[17] Evidently, this process does not
contribute towards the racemization of the stereogenic centre.
However, deuterium incorporation at the γ’-position can
preferentially occur via the mechanism shown in part-b, Scheme
3. The enhanced acidity of γ’-protons in G promotes easy
enolization to H. Subsequent deuteration generates either di- or
tri-deuterated products (I or J) depending on the substitution
pattern. This process effectively explains the most likely reason
for obtaining the products either as racemates or in low
enantioselectivities during the screening with chiral phosphines.
Alternatively, erosion in the ee is possible if the cyclization is
reversible before phosphine leaves. But further studies are
required to effectively explain this hypothesis.
In order to gain evidence in support of deuterium
incorporation occurring during the reaction, ynones (1a, 3a, and
3e) and final products (2a and 4a) were subjected to the reaction
conditions mentioned in Table 4. These results strongly indicate
that deuterium incorporation at γ’-position did not occur during
the product formation (part-a, Scheme 3) or during/after the
isolation of the product; but it occurred during the reaction (part-
b, Scheme 3).
[2]
a) F. Silva, M. Sawicki, V. Gouverneur, Org. Lett. 2006, 8, 5417; b) Y. K.
Chung, G. C. Fu, Angew. Chem. Int. Ed. 2009, 48, 2225; c) Z. Lian, M.
Shi, Eur. J. Org. Chem. 2012, 581; d) L. Yang, P. Xie, E. Li, X. Li, Y.
Huang, R. Chen, Org. Biomol. Chem. 2012, 10, 7628; e) L. Liang, E. Li,
P. Xie, Y. Huang, Chem. Asian J. 2014, 9, 1270; f) L. Zhu, Y. Xiong, C.
Li, J. Org. Chem. 2015, 80, 628. For selected reviews on
organocatalytic C(sp3)-H functionalizations, see: g) P. R. Schreiner, A.
A. Fokin, Chem. Rec. 2004, 3, 247; h) Y. J. Park, J. –W. Park, C. –H.
Jun, Acc. Chem. Res. 2008, 41, 222; i) S. C. Pan, Beilstein J. Org.
Chem. 2012, 8, 1374; j) L. Wang, J. Xiao, Adv. Synth. Catal. 2014, 356,
1137; k) C. Zheng, S. –L. You, RSC Adv. 2014, 4, 6173; l) C. Borie, L.
Ackermann, M. Nechab, Chem. Soc. Rev. 2016, 45, 1368.
[3]
[4]
[5]
H. Kuroda, I. Tomita, T. Endo, Org. Lett. 2003, 5, 129.
J. E. Wilson, J. Sun, G. C. Fu, Angew. Chem. Int. Ed. 2010, 49, 161.
a) D. B. Ramachary, C. Venkaiah, P. M. Krishna, Org. Lett. 2013, 15,
4714; b) D. B. Ramachary, P. M. Krishna, T. P. Reddy, Org. Biomol.
Chem. 2016, 14, 6413.
[6]
[7]
[8]
[9]
B. Satpathi, S. S. V. Ramasastry, Angew. Chem. Int. Ed. 2016, 55,
1777.
Y. Liu, M. Nappi, E. Arceo, S. Vera, P. Melchiorre, J. Am. Chem. Soc.
2011, 133, 15212.
a) X. Chen, S. Yang, B. –A. Song, Y. R. Chi, Angew. Chem. Int. Ed.
2013, 52, 11134; b) J. Xu, S. Yuan, M. Miao, Org. Lett. 2016, 18, 3822.
L. Zhou, B. B. Xu, J. Zhang, Angew. Chem. Int. Ed. 2015, 54, 9092.
Scheme 4. Control experiments to prove the occurrence of an in situ
[10] For some interesting organocatalytic versions involving oQDM
intermediates, see: a) A. Raja, B. –C. Hong, G. H. Lee, Org. Lett. 2014,
16, 5756, b) L. Dell’Amico, A. Vega-Peꢀaloza, S. Cuadros, P.
Melchiorre, Angew. Chem. Int. Ed. 2016, 55, 3313. c) V. Chintalapudi,
E. A. Galvin, R. L. Greenaway, E. A. Anderson, Chem. Comm. 2016,
52, 693.
racemization.
In summary, we present a new organophosphine catalyzed
γ’[C(sp3)-H]-functionalization/intramolecular hydroalkylation of
ynones leading to the synthesis of cyclopenta[b]annulated
heteroarenes. This method also establishes an unprecedented
carbocyclization of heteroaryl-based ortho-quinodimethanes
(oQDMs). Deuterium labelling experiments provided sufficient
evidence to support the racemization occurring during the
transformation. We believe that the present study can have
potential implications on the development of newer
organocatalytic C(sp3)-H-functionalization pathways. Efforts to
apply the insights gained through this study to newer substrate
designs, and application of the present strategy in the total
synthesis of natural products are in progress.
[11] a) C. D. Jones, M. G. Jevnikar, A. J. Pike, M. K. Peters, L. J. Black, A.
R. Thompson, J. F. Falcone, J. A. Clemens, J. Med. Chem. 1984, 27,
1057; b) P. Dallemagne, L. P. Khanh, A. Alsaidi, I. Varlet, V. Collot, M.
Paillet, R. Bureau, S. Rault, Bioorg. Med. Chem. 2003, 11, 1161; c) J.
M. Richter, Y. Ishihara, T. Masuda, B. W. Whitefield, T. Llamas, A.
Pohjakallio, P. S. Baran, J. Am. Chem. Soc. 2008, 130, 17938; d) B.
Satpathi, S. S. V. Ramasastry, Angew. Chem. Int. Ed. 2016, 55, 1777;
e) Manisha, S. Dhiman, J. Mathew, S. S. V. Ramasastry, Org. Biomol.
Chem. 2016, 14, 5563 and references cited therein.
[12] For selected articles on intermolecular hydroalkylation of alkenes and
alkynes, see: a) M. Rueping, B. J. Nachtsheim, A. Kuenkel, Synlett,
2007, 9, 1391; b) c) A. M. Suess, G. Lalic, Synlett 2016, 27, 1165; c) X.
–Y. Lu, J. –H. Liu, X. Lu, Z. –Q. Zhang, T. J. Gong, B. Xiao, Y. Fu,
Chem. Comm. 2016, 52, 5324. For intramolecular hydroakylation of
alkenes and alkynes, see: d) X. Wang, T. Pei, X. Han, R. A.
Widenhoefer, Org. Lett. 2003, 5, 2699; e) S. J. Pastine, K. M. McQuaid,
D. Sames, J. Am. Chem. Soc. 2005, 127, 12180; f) U. Biermann, R.
Koch, J. O. Metzger, Angew. Chem. Int. Ed. 2006, 45, 3076; g) Y. –P.
Xiao, X. –Y. Liu, C. –M. Che, Angew. Chem. Int. Ed. 2011, 50, 4937; h)
P. Pardo, A. Fernandez, F. J. Fananas, F. Rodriguez, Adv. Synth. Catal.
2012, 354, 2141.
Acknowledgements
This work was supported financially by IISER Mohali. We thank
IISER Mohali for NMR, mass, and X-ray facilities. M.R. thanks
UGC, New Delhi for JRF and J.G. thanks IISER Mohali for
postdoctoral fellowship.
[13] See Supporting Information for details.
[14] The crystal structure has been deposited at the Cambridge
Crystallographic Data Centre, and the deposition number CCDC
1483548 (for 2a) has been assigned. See ESI for details.
Keywords: hydroalkylation • organophosphines • heterocycles •
ynones • cyclopentannulation
[15] No other solvent combination (with D2O) furnished the desired products
(see Table 1 for the solvents that facilitate this reaction).
[1]
Selected reviews on phosphine catalysis: a) X. Lu, C. Zhang, Z. Xu,
Acc. Chem. Res. 2001, 34, 535; b) D. H. Valentine, J. H. Hillhouse,
Synthesis 2003, 317; c) J. L. Methot, W. R. Roush, Adv. Synth. Catal.
[16] a) J. L. Methot, W. R. Roush, Org. Lett. 2003, 5, 4223; b) D. Gonzalez-
Cruz, D. Tejedor, P. de Armas, F. Garcia-Tellado, Chem. Eur. J. 2007,
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13, 4823; c) Y.-Q. Jiang, Y.-L. Shi, M. Shi, J. Am. Chem. Soc. 2008,
130, 7202.
[17] Y. Xia, Y. Liang, Y. Chen, M. Wang, L. Jiao, F. Huang, S. Liu, Y. Li, Z.-
X. Yu, J. Am. Chem. Soc. 2007, 129, 3470.
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Entry for the Table of Contents
COMMUNICATION
Moluguri Raghu, Jagdeep Grover, S. S.
V. Ramasastry*
Page No. – Page No.
Cyclopenta[b]annulation of
Heteroarenes via Organocatalytic
γ’[C(sp3)-H] Functionalization of
Ynones
Redox by an organophosphine!: Organocatalytic intramolecular hydroalkylation
of ynones has been achieved. Nucleophilic addition of an organophosphine to the
designed ynones generate heteroaryl-based ortho-quinodimethanes (oQDMs) via
γ’[C(sp3)-H] functionalization, which undergo annulative hydroalkylation leading to
the formation of a diverse set of cyclopentannulated heteroarenes in good yields
and excellent stereoselectivities.
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