Access to pyrrolo[2,1-: A] isoindolediones from oxime acetates and ninhydrin via Cu(i)-mediated domino annulations

Article abstract of DOI:10.1039/d0ob00058b

A copper-mediated domino condensation reaction of readily accessible oxime acetates with ninhydrin is reported to afford pyrrolo[2,1-a]isoindolediones via new C-C & C-N bond formations. A wide range of oxime acetates were shown to generally participate in the reaction to produce the condensed products in excellent yields. The necessary control experiments were performed and the mechanism is proposed to involve sequentially the formation of iminium radical via Cu-mediated N-O bond cleavage of oxime acetates, addition of the radical to ninhydrin and rearrangement via ring expansion.

Full text of DOI:10.1039/d0ob00058b

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: S. R. Bathula, A.
upare, N. K. Chouhan, R. Andhavaram and S. Balasubramanian, Org. Biomol. Chem., 2020, DOI:
10.1039/D0OB00058B.
Volume 15
Number 47
21 December 2017
Pages 9945-10124
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
Accepted Manuscripts are published online shortly after acceptance,
rsc.li/obc
before technical editing, formatting and proof reading. Using this free
service, authors can make their results available to the community, in
citable form, before we publish the edited article. We will replace this
Accepted Manuscript with the edited and formatted Advance Article as
soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes to the
text and/or graphics, which may alter content. The journal’s standard
Terms & Conditions and the Ethical guidelines still apply. In no event
ISSN 1477-0520
PAPER
I . J. Dmochowski et al.
Oligonucleotide modifi cations enhance probe stability for
shall the Royal Society of Chemistry be held responsible for any errors
single cell transcriptome in vivo analysis (TIVA)
or omissions in this Accepted Manuscript or any consequences arising
from the use of any information it contains.
rsc.li/obc

Please do not adjust margins
Page 1 of 4
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/D0OB00058B
COMMUNICATION
Access to pyrrolo[2,1-a]isoindolediones from oxime acetates and
ninhydrin via Cu(I)-mediated domino annulations
Atul Upare,a,b Neeraj Kumar Chouhan,a,b Andhavaram Ramaraju,a Balasubramanian Sridhar,c and
Surendar Reddy Bathula*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
(scheme 1a) via N1, C2, and C3 trifunctionalization of indoles in
one-pot manner.10 Wei group has synthesized spiropyrrolines from
Abstract: A copper-mediated domino condensation reaction of
readily accessible oxime acetates with ninhydrin is reported to
afford pyrrolo[2,1-a]isoindolediones via new C-C & C-N bond
formations. A wide range of oxime acetates were shown to
generally participate in the reaction to produce the condensed
products in excellent yields. The necessary control experiments
were performed and mechanism is proposed to involve
sequentially the formation of iminium radical via Cu-mediated
N−O bond cleavage of oxime acetates, addition of the radical to
ninhydrin and rearrangement via ring expansion.
Oxime O-ethers and esters are emerging as first-line synthons in
modern heterocyclic chemistry because of their ready availability
and easily activatable N-O bonds.1-4 O-acetyl oximes can generate
enamines in situ via copper-mediated N–O bond activation either
by oxidative addition or by radical process.5 The resultant enamines
undergo [3+3] or [3+2]-type condensation reactions with suitable
electrophiles such as aldehyde, malononitrile, β-ketoesters,
carbonyl–amine condensates, alkenes, isothiocyanates and alkynes
to produce six and five-membered N-heterocycles.6 In this regard,
several research groups have reported the utility of O-acyl oximes
for the construction of a wide variety of N-heterocyclic compounds.
For instance, Yoshikai et al. have reported the synthesis of pyridines
from O-acyl oximes and α,β-unsaturated imines.7 Jiang et al. have
reported multiple methods for the synthesis of various N-
heterocycles such as pyrrole, imidazo[1,2-a]pyridine, pyrazole,
pyridine and 2-aminothiazole from O-acyl oxime and copper (I)
catalysts.8 Guan and co-worker have developed synthetic methods
for symmetrical pyridines and pyrroles from O-acyl oxime using
CuBr as catalyst.9 Deng group have reported the construction of
pyrazolo[1,5-a]indole derivatives from O-acyl oxime and indole
Scheme 1. Copper-mediated synthesis of fused and spiro ring via
oxime acetates.
O-acyl oximes and alkenes via Cu (I) catalyzed intermolecular
cyclization reaction (scheme 1b).11 Guan-Wu Wang has developed
Cu(I)-catalyzed facile and efficient synthetic protocol for 1-
fulleropyrrolines by heteroannulation of C60 with O-acyl oxime
(scheme 1c).12 Furthermore, our group has reported the synthesis
of mono- and disubstituted pyrimidine and 4-functionalised
quinolines from oxime acetates.13 Along this line, further exploring
the reactivity of O-acyl oximes, we herein report a copper-mediated
[3+2] domino cyclization of oxime acetates and ninhydrin for the
synthesis of novel 9b-hydroxy-1H-pyrrolo[2,1-a]isoindolediones
(scheme 1d). Ninhydrin is
a powerful electrophile having
widespread application in organic and bio-organic sciences.14
We have initiated our study by investigating the Cu-
mediated domino cyclization of acetophenone oxime acetate
a. Department of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of
Chemical Technology, Hyderabad 500007, India E-mail: bsreddy@iict.res.in
http://www.iictindia.org/staffprofiles/staffprofile.aspx?qry=1836
b. AcSIR ( Academy of Scientific & Innovative Research), Ghaziabad, 201 002, India
c. X-ray Crystallography Division, CSIR-Indian Institute of Chemical
Technology, Tarnaka, Hyderabad 500007, India
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
(
1a, 1mmol) and ninhydrin (2, 1 mmol) in DMSO at 80 °C. We
were pleased to find that the 9b-hydroxy-3-phenyl-1H-
pyrrolo[2,1-a]isoindole-1,5(9bH)-dione 3a was obtained in 20%
yield in the presence of 10 mol% of CuI in open air (Table 1,
entry 1). To our delight, increase in catalyst loading to 30 mol%
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 4
COMMUNICATION
Journal Name
could enhance the yield of 3a to 35% (entry 2). Further successfully gave corresponding pyrrolo[2,1-a]isoindVoielewdAirotinclee O3nil-in3el
DOI: 10.1039/D0OB00058B
increase in catalyst loading up to 100 mol% did not show any with 55-75% yield. In addition, ortho-chloro acetophenone oxime
improvement in the yield (entry 3). Encouraged by this result, acetate also underwent the desired transformation to give the
we have increased the reaction temperature to 100 °C and 3a corresponding pyrrolo[2,1-a]isoindoledione 3m in 60 % yield.
was formed in 50 % yield. Further increase in the reaction Furthermore, 3,4 dimethoxy acetophenone oxime acetate 1n
temperature did not show any significant effect on the product proceeded smoothly to give the desired product 3n 77% yield
.
yield (entry 5). Next, various copper catalysts, such as CuCl, These results indicate that the electronic (except nitro and
CuBr, CuCl2, CuBr2 and Cu(OAc)2, were screened to find out the trifluromethyl groups) as well as steric factors are not
effect of copper salts on the reaction efficiency (entries 6-10). significantly affecting the conversion. Inspired by these results
CuBr was found to be the highest efficacious catalyst for the we have tested the fate of 2-substituted acetophenone oxime
conversion, producing the desired 9b-hydroxy-3-phenyl-1H- acetates under the standard reaction conditions.
pyrrolo[2,1-a]isoindole-1,5(9bH)-dione 3a in 80% yield (entry Propiophenone, hexanophenone and 2-phenylacetophenone
7). Moreover, changing the solvent to DMF was less efficient oxime acetates (1o-1q) underwent the desired conversion to
(entry 11) and no product formation was observed in 1,4- produce the corresponding 2-substituted Pyrrolo[2,1-a]
dioxane, toluene and THF (entry 12-14). In control experiment Isoindolediones 3o (76%), 3p (70%) and 3q (73%) in good yields.
no product formation was observed in the absence of catalyst Moreover, α-tetralone and 2-acetylfluorene oxime acetates were
(entry 15).
tolerated in the reaction and afforded the corresponding products
3r and 3s in 65 and 68% yield.
Table 1. Optimisation of the reaction conditions.a
Table 2. Synthesis of various pyrrolo[2,1-a]isoindolediones from
aromatic oxime acetate.a
a
Reaction conditions: 1a (1 mmol), 2 (1 mmol),catalyst (30 mol%),
heated in DMSO (3 mL), at 100 °C for 4h. (N.R. = not reacted)
Having optimized reaction conditions in hand (table 1,entry 7),
we subsequently examined the scope of this transformation with
the broad range of ketoxime acetates and result are summarised in
Table 2. This reaction exhibited good functional group tolerance
and demonstrated to be a practical method for the synthesis of
various pyrrolo[2,1-a]isoindolediones. Under the standard reaction
conditions para-methyl, methoxy, chloro, bromo, nitro, t-butyl and
phenyl substituted acetophenone oxime acetate produced
corresponding pyrrolo[2,1-a] isoindoledione 3b-3h in moderate to
good yields (58-88%). Also, meta-methoxy, chloro, bromo and
trifluromethyl substituted acetophenone oxime acetates
a Reaction conditions:
1 (1 mmol), 2 (1 mmol),CuBr (30 mol%),
heated in DMSO (3 mL), at 100 °C for 4h.
Next, a series of heteroaromatic ketoxime acetates (1t
-
1y) were investigated to extend the substrate scope. To our
delight, thiophene, furan, and pyridine heterocycle based
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Page 3 of 4
Organic & Biomolecular Chemistry
Journal Name
COMMUNICATION
ketoxime acetates reacted smoothly to give the desired
product 3t
To understand the reaction mechanism some control
DOI: 10.1039/D0OB00058B
3v in 65-71% yield. Moreover, substituted experiments were conducted as shown in Scheme 3. Initially, we
View Article Online
-
thiophene oxime acetate such as 2,5 dimethyl, chloro, bromo conducted a reaction in the presence of BHT to rule out any
also reacted smoothly under standard conditions to give the radical mediation (Scheme 3, eq. 1). When BHT was added to the
desired product 3w-3y in 67-72% yield. Finally, 3,4- reaction no product formation was observed, but 28% starting
methylenedioxyacetophenone oxime acetate also gave the material was recovered and 20% acetophenone was also
corresponding product 3z in 73% yield.
Scheme 3: Control experiments. (n.d.= not detected)
isolated. Similar results were obtained with another radical
scavenger TEMPO (eq. 2). These results indicate that the
Figure 1. Structure of compound 3d (CCDC 1954828) was
reaction proceeded through a radical pathway. Furthermore,
confirmed by single crystal X-ray diffraction analysis.
replacement of acetophenone oxime acetate with
acetophenone and ammonium acetate under the standard
Scheme 2: synthetic utility
reaction condition (eq. 3) failed to produce the desired product,
O
indicating the importance of oxime acetate.
NaBH4
N
8,9,11
MeOH
On the basis of the above result and previous studies
a
O
HO
HO
possible mechanism for this transformation is proposed in
Scheme 4. Initially, N-O bond of O-acyl oximes was activated by
Cu(I) via single-electron-transfer reaction to produce iminium
N
(+)4 (84 %)
Ph
P
O
Ph
Ph
HO
O
radical
intermediate B 8,11
constructed a new C–C bond to afford intermediate
A
,
which rapidly isomerised to carbon radical
Addition of intermediate with ninhydrin
. This oxy
O
O
N
.
B
DCM, 48h
reflux
3b
C
HO
radical must have prompted the C-C bond cleavage to give strain
free acyl radical which might have reacted on imine N towards
EtO2C
5 (77 %), (dr =10:1)
stable benzyl radical intermediate D 8f
intermediate was oxidised by Cu(II) to afford intermediate
with the regeneration of Cu(I).8a,8e After the expulsion of H+,
intermediate was then transformed to intermediate which
.
Subsequently, the
D
E
To expand the synthetic utility of our developed protocol, we
performed reactions using 3b as the starting materials to create
diverse analogues of the title compounds (Scheme 2). We first
reduced the keto group of 3b with NaBH4 in a chemoselective
E
F
cyclized to the desired product 3a through a hemiaminal
formation.
N
O
O
O
O
manner. Surprisingly the reduction afforded the product
4 as a
HO
HO
OAc
Ph
NH
O
single isomer in 84% yield. The hydroxy chelated borohydride
might have reduced it in an anti fashion to give the trans isomer
selectively. However, we are unable to prove the structure
unambiguously as we could not take the assistance of NOSY as
there is no appropriate adjacent proton available. Further, we
were able to perform Wittig reaction on the keto group of 3b
N
A
Ph
1a
Ph
B
2
O
O
Ph
N
NH
Cul
Cull
OH
Ph
C
O
O
O
3a
O
HN
O
O
using ethyl (triphenylphosphoranylidene)acetate to obtain
5
Ph
HN
with 10:1 dr in 77% yield. Conjugation and the probable
hydrogen bonding between OH and COOEt might have afforded
the stable trans product (Z-) as the major isomer.
O
Ph
O
O
F
HN
D
-H+
O
Ph
E
O
O
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 4
COMMUNICATION
Journal Name
Scheme 4: Possible reaction mechanism.
(e) X. Tang, Z. Zhu, C. Qi, W. Wu, and H. JiaVniegw, OArrtigcl.eLOentlitn.e,
DOI: 10.1039/D0OB00058B
2016, 18, 180. (f) J. L. Bullington and J. H. Dodd, J.
In conclusion, a copper-mediated annulation reaction of
readily accessible oxime acetates with ninhydrin is reported to
give pyrrolo[2,1-a]isoindolediones via an N-O bond cleavage and
C-C & C-N bond formations. The necessary control experiments
were performed to establish the mechanism. A wide range of
oxime acetates were shown to generally participate in the
reaction to produce the condensed products in excellent yields.
This work was supported by DBT (GAP0556). We are thankful
to the NMR and Mass divisions of CSIR-IICT for providing the
analytical facilities. We thank Director CSIR-IICT fo the support
(IICT/Pubs./2020/035). A.U. and N.K.C. thanks CSIR for the PhD
fellowship.
Heterocyclic chem., 1998, 35, 397
9. (a) Z. Ren, Z. Zhang, B. Yang, Y. Wang, and Z. Guan, Org.
Lett., 2011, 13, 5394; (b) L. Ran, Z. Ren, Y. Wang and Z.
Guan, Green Chem., 2014, 16, 112.
10. H. Huang, J. Cai, X. Ji, F. Xiao, Y. Chen, and G. Deng,
Angew. Chem. Int. Ed., 2016, 55, 307.
11. B. Zhao, H. Liang, J. Yang, Z. Yang, and Y. Wei, ACS Catal.,
2017, 7, 5612.
12. S. Jiang, Y. Su, K. Liu, Q. Wu, and G. Wang, Chem.
Commun., 2015, 51, 6548.
13. (a) A. Upare, S. Pochampalli, R. Kore, K. Sharma, and B. S.
Reddy, Tetrahedron Lett., 2018, 59, 2430; (b) A.
Ramaraju, N. Chouhan, R. Owk, B. Sridhar, and B. S.
Reddy, Eur. J. Org. Chem., 2018, 23, 2963.
Conflicts of interest
There are no conflicts to declare.
14. (a) M. M. Joullie, T. R. Thorny and N. H. Nemeroff,
Tetrahedron, 1991, 47, 8791; (b) D. J. McCaldin Chem.
Rev., 1960, 60, 1, 39.
Notes and references
1. For reviews, see: (a) A. Y. Sukhorukov and S. L. Ioffe,
Chem.Rev., 2011, 111, 5004; (b) H. Huang, X. Ji, W. Wua
and H. Jiang, Chem. Soc. Rev., 2015, 44, 1155; (c) H.
Huang, J. Cai and G. Deng, Org. Biomol. Chem., 2016, 14,
1519; (d) J. Li, Y. Hu, D. Zhang, Q. Liu, Y. Dong and H.
Liu, Adv. Synth. Catal., 2017, 359, 710
.
2. (a) K. Narasaka and M. Kitamura, Eur. J. Org. Chem.,
2005, 21, 4505; (b) S. Zaman, K. Mitsuru and A. D. Abell,
Org. Lett., 2005, 7, 609; (c) T. Gerfaud, L. Neuville and J.
Zhu, Angew. Chem. Int. Ed., 2009, 48, 572; (d) Y. Tan and
J. F. Hartwig, J. Am. Chem. Soc., 2010, 132, 3676.
3. (a) P. C. Too, Y. Wang and S. Chiba, Org. Lett., 2010, 12
,
5688; (b) X. Zhang, D. Chen, M. Zhao, J. Zhao, A. Jia and
X. Li, Adv. Synth. Catal., 2011, 353, 719; (c) P. C. Too, T.
Noji, Y. J. Lim, X. Li and S. Chiba, Synlett, 2011, 19, 2789.
4. (a) R. Chinnagolla, S. Pimparkar and M. Jeganmohan, Org.
Lett., 2012, 14, 3032; C. Kornhaaß, J. Li and L.
Ackermann, J. Org. Chem. 2012, 77, 9190.
5. (a) C. Zhu, H. Zeng, F. Chen, C. Liu, R. Zhu, W. Wu, and H.
Jiang, Org. Chem. Front., 2018, 5, 571 (b) S. Liu and L. S.
Liebeskind, J. Am. Chem. Soc., 2008, 130, 6918; (c) H.
Liang, Z.-H. Ren,Y.Y. Wang and Z.-H. Guan, Chem. Eur. J.,
2013, 19, 9789; (d) Q. Wu, Y. Zhang and S. Cui, Org.
Lett., 2014, 16, 1350
6. W. Du, M. Zhao, Z. Ren, Y. Wang and Z. Guan Chem.
Commun., 2014, 50, 7437.
7. (a) Y. Wei and N. Yoshikai, J. Am. Chem. Soc., 2013, 135
,
3756; (b) W. W. Tan, Y. J. Ong and N. Yoshikai, Angew.
Chem. Int. Ed., 2017, 56, 8240.
8. (a) X. Tang, L. Huang, C. Qi, W. Wu and H. Jiang, Chem.
Commun., 2013, 49, 9597; (b) H. Huang, X. Ji, X. Tang,
M. Zhang, X. Li, and H. Jiang, Org. Lett., 2013, 15, 6254;
(c) X. Tang, L. Huang, J. Yang, Y. Xu, W. Wu and H. Jiang,
Chem. Commun., 2014, 50, 14793; (d) H. Jiang, J. Yang,
X. Tang, J. Li, and W. Wu; J. Org. Chem., 2015, 80, 8763;
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins