Cyclopropenones in the synthesis of indolizidine, pyrrolo[2,1-a]isoquinoline and indolizino[8,7-b]indole alkaloids

Article abstract of DOI:10.1016/j.tet.2020.131570

An attempted synthesis of the indolizidine natural product castanospermine resulted in the successful addition of cyclopropenone to a sugar-derived poly-hydroxylated cyclic imine to give an indolizidinone product, but with the installation of an extra hydroxy group at the castanospermine 8a-bridgehead position. This was also observed in our previous approach to the australine and hyacinthacine pyrrolizidine natural products. The same oxidative phenomenon occurred during the synthesis of pyrrolo[1,2-a]isoquinolines from the reaction of aldimine dihydroisoquinolines with cyclopropenones, whereas ketimine based dihydroisoquinolines gave pyrrolo[1,2-a]isoquinolines without bridgehead oxidation. These results may have some significance for the origins of the bridgehead hydroxy natural products jenamidine B₁/B₂, clazamycin A/B and legonmycin A/B. The precursor cyclic aldimine for the synthesis of the indolizino[8,7-b]indoles gave dimeric indolizino[8,7-b]indoles, whereas the corresponding cyclic ketimines behaved as expected and gave the indolizino[8,7-b]indole core after reaction with cyclopropenones.

Full text of DOI:10.1016/j.tet.2020.131570

Tetrahedron 76 (2020) 131570
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Cyclopropenones in the synthesis of indolizidine, pyrrolo[2,1-a]
isoquinoline and indolizino[8,7-b]indole alkaloids
,
Faisal Jamshaid a b, Vishnu V.R. Kondakal a, C. Declan Newman a, Rhianne Dobson a,
a
a
a
a
a, *, 1
~
Heidi Joao , Craig R. Rice , Joseph M. Mwansa , Bimod Thapa , Karl Hemming
a Department of Chemical Sciences, School of Applied Sciences, University of Huddersfield, Queensgate, Huddersfield, HD1 3DH, United Kingdom
b FangYuan Pharmaceutical Company, No. 1018, Liaohe Road, Xinbei Zone, Changzhou, Jiangsu, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An attempted synthesis of the indolizidine natural product castanospermine resulted in the successful
addition of cyclopropenone to a sugar-derived poly-hydroxylated cyclic imine to give an indolizidinone
product, but with the installation of an extra hydroxy group at the castanospermine 8a-bridgehead
position. This was also observed in our previous approach to the australine and hyacinthacine pyrroli-
zidine natural products. The same oxidative phenomenon occurred during the synthesis of pyrrolo[1,2-a]
isoquinolines from the reaction of aldimine dihydroisoquinolines with cyclopropenones, whereas keti-
mine based dihydroisoquinolines gave pyrrolo[1,2-a]isoquinolines without bridgehead oxidation. These
results may have some significance for the origins of the bridgehead hydroxy natural products jena-
midine B1/B2, clazamycin A/B and legonmycin A/B. The precursor cyclic aldimine for the synthesis of the
indolizino[8,7-b]indoles gave dimeric indolizino[8,7-b]indoles, whereas the corresponding cyclic keti-
mines behaved as expected and gave the indolizino[8,7-b]indole core after reaction with
cyclopropenones.
Received 17 July 2020
Received in revised form
26 August 2020
Accepted 1 September 2020
Available online 6 September 2020
Keywords:
Indolizidine
Pyrroloisoquinoline
Indolizinoindole
Castanospermine
Cyclopropenone
Oxidation
© 2020 Elsevier Ltd. All rights reserved.
1. Introduction
products that are distinguished by the presence of a bridgehead
hydroxy group such as that present in bohemamine D 9 [10],
Pyrrolo-fused alkaloids (see Fig. 1) with a nitrogen atom at the
ring junction are a large and diverse class of natural products. Of
particular interest to our research are the poly-hydroxylated
indolizidines [1,2] such as the antiviral and glycosidase inhibiting
iminosugar castanospermine 1 [1,3,4], and the poly-hydroxylated
pyrrolizidines [1,5] such as the glycosidase inhibitor hyacintha-
cine A2 2 [1,6,7] and the glucosidase inhibitor australine 3 [1,8,9].
The pyrrolizidinone class of alkaloid natural products is also of
interest and includes the marine-derived bohemamine 4 and
jenamidine C 10 [11], the related antitumour imino clazamycins A
and B 11 [18], and the recently identified legonmycins A and B 12
and 13 [19], as well as jenamidines B1/B2 6 [11], from above. These
latter species (6, 9e13) are rare amongst the pyrrolizidine natural
products in that they are alkaloid natural products of bacterial
origin rather that plant origin. It is of interest that the biosynthesis
of these bacterial natural products has recently attracted attention
[19,20] and that it was established that the bridgehead-OH species
(6, 9, 10, 12 and 13) are derived from a late stage biosynthetic
oxidation of the corresponding naturally occurring bridgehead-H
species, such as compounds 5, 14 and 15, the biosynthetic origins
of which were also elucidated. Our own work [21,22], and that of
others [23e26] (as discussed later) suggests that an additional
origin for the bridgehead-OH species is worthy of consideration
whereby aerial oxidation might be responsible for the conversion of
the bridgehead-H alkaloid into the bridgehead-OH alkaloid.
related analogues [10], the antiproliferative jenamidines A1/A2
5
[11] and jenamidines B1/B2 6 [11]. There is also great literature in-
terest in the pyrroloisoquinolines such as the antitumour com-
pound crispine 7 [12e15], and the indolizinoindoles including the
potent anti-Leishmania, antinociceptive harmicine 8 [15e17].
Within the pyrrolizidinone class there is a sub-set of natural
In previous work, we have shown that a range of 5- and 6-
membered ring cyclic aldimines 16 (n ¼ 1 or 2, Scheme 1) un-
dergo reaction with cyclopropenones 17 to produce the fused
bicyclic bridgehead-OH species 18 (with X-ray crystallographic
* Corresponding author.
E-mail address: k.hemming@hud.ac.uk (K. Hemming).
1
Dedicated to Professor Richard Taylor in celebration of his 70th birthday.
https://doi.org/10.1016/j.tet.2020.131570
0040-4020/© 2020 Elsevier Ltd. All rights reserved.

2
F. Jamshaid et al. / Tetrahedron 76 (2020) 131570
core of the clazamycin, jenamidine, bohemamine and legonmycin
natural products 6 and 9e13. Although we noted at the time [22]
that this observation may account for the origins of the jenamidine
B1/B2 bridgehead-OH moiety (by aerial oxidation of jenamidine A1/
A2), we feel that a reiteration of this is worthwhile given the more
recent biosynthetic reports [19,20]. It is notable that during the
isolation of legonmycins A and B 12/13, the presence of the corre-
sponding non-hydroxy systems 14/15 was observed [19]. It is
possible in each of these cases that an alternative or additional
pathway for the formation of the bridgehead-OH compound could
be the aerial oxidation of the bridgehead-H species.
During our original work [22], we attempted an approach to the
hyacinthacine and australine natural products 2 and 3 starting from
the imine 20 and cyclopropenone (Scheme 2). We found that
oxidation led to the pyrrolizidinone 22 as the only isolable product,
and were unable to isolate the proposed intermediate 21. In some
much earlier work [27], Eicher had shown that pyrroloisoquino-
lines could be accessed from the reaction of cyclic ketimines and
diphenylcyclopropenone (DPCP), but observed only the expected
bridgehead-H outcome with the single cyclic aldimine that was
studied, and reported no additional oxidation. On the basis of this
rich history, and the ongoing interest in these heterocyclic systems,
we are continuing to explore cyclopropenone based routes for the
synthesis of natural products. In this manuscript, we will discuss
the results of our attempts to access compounds 1, 7, 8 and ana-
logues via the reaction of cyclic aldimines and ketimines with
cyclopropenones.
2. Results and discussion
The natural product that we targeted first was castanospermine
1. In order to access this, we attempted to produce the imine 24
from the previously reported [28] azide 23, as shown in Scheme 3.
We subjected the azido-aldehyde 23 to a two-step Staudinger aza-
Wittig ring closure to give the unstable and previously unreported
cyclic aldimine 24. All attempts to produce indolizidine 25 from the
reaction of imine 24 with the parent unsubstituted cyclopropenone
[29] were unsuccessful, an outcome that we attribute to a combi-
nation of the instability of the imine 24 together with the instability
of cyclopropenone, which was generated in-situ from the acetal 26.
The attempted synthesis of indolizidinone 27 from the reaction of
imine 24 with the stable, commercially available diphenylcyclo-
propenone was also unsuccessful, indicating that the formation,
stability or reactivity of the imine 24 was the main issue.
Fig. 1. Pyrrolo-fused alkaloids.
Based upon our observation that imine 24 was insufficiently
stable, we explored the use of the alternative imine 32 (Scheme 4).
We reasoned that we could generate the imine, although unknown,
in one step from the known [30,31] stable nitrone 31 rather than
Scheme 1. The synthesis of bridgehead hydroxy-pyrrolizidinones [22].
confirmation) rather than the expected bridgehead-H species 19
[22]. As shown in Scheme 1, we proposed that the reaction pro-
ceeded via the expected [21] regioselective formal [3 þ 2]-cyclo-
addition process to produce species 19 which then underwent
oxidation. We observed this process in a total of nine examples. A
particular highlight of our approach is the ability to install with ease
the bridgehead-OH and pyrrolizidinone ring that is present at the
Scheme 2. An Approach to Australine and Hyacinthacine [21].

F. Jamshaid et al. / Tetrahedron 76 (2020) 131570
3
in 43% yield. The key evidence for the formation of the 8a-hydroxy
compound 33 (rather than non-oxidized alternative compound 34)
was the presence of a quaternary carbon at 92.44 ppm in the 13C
NMR spectrum (and the absence of the expected CH), a clear OH in
the 1H NMR and infra-red spectra, and an additional oxygen atom
in the high resolution mass spectrum. Compound 33 was isolated
as a single major diastereoisomer (~95% purity), but we were not
able to determine the stereochemistry at the bridgehead. We
attribute the formation of compound 33 to the aerial oxidation of
the desired product 34, a process that, as discussed above, we have
observed before in our work with pyrrolizidines related to the
clazamycin, jenamidine, and legonmycin natural products. All at-
tempts to isolate compound 34 or react it in-situ in the absence of
oxygen were unsuccessful. We also attempted to reduce compound
33 into useful analogues of castanospermine, but were unsuccess-
ful. Whilst this halted our attempts to access the natural product
castanospermine, we note that this result offers further evidence of
the facile nature of this type of bridgehead oxidation (see later for a
mechanistic discussion).
Scheme 3. Attempted Synthesis of Castanospermine e Route 1. Reagents and Condi-
tions: (a) PPh3, THF or CHCl3, 15 min at RT, then reflux, 5 h; (b) diphenylcycloprope-
none (see text); (c) acetone, Hþ, - 10 ꢀC e RT, overnight.
Reagents and Conditions: (a) TBDPSONH2, toluene, PPTS, reflux,
3 h; (b) MeSO2Cl, Et3N, CH2Cl2, 0 ꢀC e RT, 3h; (c) THF, 4 Å MS, TBAF,
30 min, reflux; (d) THF, PnBu3, 65 ꢀC, 48 h; (e) cyclopropenone,
MeCN, - 10 ꢀC e RT, overnight.
Having previously explored the reactivity of simple and complex
3,4-dihydro-2H-pyrroles and simple 2,3,4,5-tetrahydropyridines
(see Introduction) and now
a
more complex 2,3,4,5-
tetrahydropyridine, and having observed bridgehead oxidation in
all cases, we next looked at dihydroisoquinolines. Our objective
here was to study a potential route to the pyrroloisoquinoline core
present in natural products such as crispine (structure 7 in Fig. 1).
The known dihydroisoquinoline 35 (X ¼ Y¼ H), shown in Table 1,
was synthesized by the bromination (NBS) and then dehydro-
bromination of tetrahydroisoquinoline [33]. Compound 35 was
nitrated (KNO3) to give the corresponding nitro compound 36
(X ¼ H, Y ¼ NO2) [33]. The dimethoxy compound 37 (X ¼ Y ¼ OMe)
was synthesized using a known [34] Pictet-Spengler reaction on
the corresponding arylethylamine and was selected for its simi-
larity to crispine 7. The reactivity of these three dihydroisoquino-
lines towards diphenylcyclopropenone 38 and the readily available
[35,36] di-(4-methoxyphenyl) and di-(4-fluorophenyl)cyclo-
propenone 39 and 40 was explored (Table 1). The nitro-compound
36 was unreactive, but the dihydroisoquinolines 35 and 37 reacted
with diarylcyclopropenones 38e40 to give adducts 41e46 which
could be isolated in 34e69% yields (Table 1) in reasonable purity
Scheme 4. Attempted Synthesis of Castanospermine: Route 2.
from the two step Staudinger aza-Wittig process used in Scheme 3.
The nitrone 31 would be deoxygenated using tri-(n-butyl)phos-
phine in a process developed by Milet, Py and Toy [32] for 5-
membered ring cyclic nitrones. We also anticipated that the
benzyl protecting groups would allow reaction conditions that are
more compatible with in-situ cyclopropenone generation from the
cyclopropene acetal 26 than was the case with the acetal-protected
precursor 24 used in Scheme 3. As shown in Scheme 4, the ring-
opened aldehyde form of the readily available [30] tribenzyl pro-
tected sugar 28 was trapped with TBDPS-protected hydroxylamine
to give the aldimine 29 [30]. Mesylation [30] of the primary alcohol
and cyclisation [31] of the intermediate 30 gave the nitrone 31 [31].
Attempts to perform this chemistry directly with unprotected hy-
droxylamine were unsuccessful due to the emergence of competing
processes upon attempted mesylation. Reaction of the nitrone 31
with tri-(n-butyl)phosphine [32] resulted in consumption of the
nitrone to give a new product, which we assume to be the cyclic
imine 32, although it was insufficiently stable to allow characteri-
sation. However, we were pleased to see that the imine was suffi-
ciently stable to undergo reaction with freshly generated
cyclopropenone to give the 8a-hydroxy substituted indolizidine 33
Table 1
The synthesis of pyrroloisoquinolines. .
Product
X
Y
Ar
% Yield
41
42
43
44
45
46
H
H
H
OMe
OMe
OMe
H
H
H
OMe
OMe
OMe
Ph
59
52
36
65
69
34
4-MeOC6H4
4-FC6H4
Ph
4-MeOC6H4
4-FC6H4
Reagents and Conditions: (a) MeCN or CHCl3, RT, 3e24 h.

4
F. Jamshaid et al. / Tetrahedron 76 (2020) 131570
from complex reaction mixtures. Compounds 42 and 43 in partic-
ular contained small amounts (<10% and <5%, respectively) of an
unidentified isomeric impurity which may be the lactam regioiso-
meric product or (see later) a ring-opened lactam. In each case the
bridgehead OH species was the only product isolated. This was
evidenced in the 13C NMR spectra of the products by a quaternary
carbon signal at 85e86 ppm for the bridgehead CeOH, and the
absence of the expected CeH signal. Infra-red spectroscopy showed
the OH signal, and high resolution mass spectrometry confirmed
the additional oxygen atom. This offers further evidence that this
bridgehead oxidation is quite general, occurring with each of the
cyclic aldimines with which we have worked. In the case of com-
pound 41, our observation is in contrast to the product that Eicher
reported, which had no bridgehead OH, as discussed above [27].
A mechanistic explanation for the formation of the bridgehead-
OH systems is proposed in Scheme 5. The first step is the expected
[21,22] and well-explored formal [3 þ 2]-cycloaddition between
the imine and the cyclopropenone to form intermediate 47. We
next propose the ready formation of a stabilized [26] captodative
free radical species 48 that allows addition of oxygen in order to
generate the hydroperoxide 49 which undergoes facile OeO bond
cleavage to give the final isolated alcohol 50. The exclusion of ox-
ygen from our reaction media did not permit the isolation or
observation of species 47, with reaction work-up always resulting in
the isolation of the oxidized products 50. It has been noted by the
Scheme 6. Literature Precedent for Bridgehead Oxidation.
Table 2
Pyrroloisoquinolines from cyclic ketimines. .
ꢀ
1
research groups of Groselj [23] and McNab [24e26] that the
Cyclic imine
R
R
Pro-duct
Ar
% Yield
oxidation of 3-hydroxy pyrroles, or their tautomeric 1H-pyrrol-
3(2H)-ones is a facile process. McNab obtained strong evidence [26]
(ESR) that these oxidations do indeed proceed via a captodative
radical such as that shown in Scheme 5. The compounds studied by
McNab’s group, 51e53, are shown in Scheme 6, and were produced
via flash vacuum pyrolysis of Meldrum’s acid derivatives, a very
different route to that detailed in our work, and all underwent the
same oxidation. These observations present clear evidence that
these bridgehead-H systems undergo facile aerial oxidation, and
that this could therefore apply to the oxidation of natural products
in the jenamidine, clazamycin and legonmycin classes.
a
a
a
a
54a
54b
54c
54d
56a
56a
56b
56c
56d
56e
56f
Me
iPr
Bn
Ph
Me
Me
CHF2
CH2F
Me
Ph
Et
(CH2)2Ph
4-ClC6H4
H
H
H
H
H
H
H
H
Me
H
H
H
H
55a
55b
55c
55d
57ai
57aii
57b
57c
57d
57e
57f
Ph
Ph
Ph
Ph
Ph
57b,c
53b
41b
27b
4-MeOC6H4
Ph
4-FC6H4
Ph
Ph
Ph
Ph
Ph
78b
d
d
d
d
56g
56h
57g
57h
The mechanistic rationale in Scheme 5 and the literature pre-
cedent in Scheme 6 mean that this oxidative process is limited to
cyclic aldimines due to the inability of the corresponding cyclic
ketimines to allow the formation of the intermediate bridgehead
radical 48. This is confirmed by the earlier work of Eicher, who
showed that dihydroisoquinoline based cyclic ketimines 54a-
d reacted with diphenylcyclopropenone to give pyrroloisoquino-
lines 55a-d (see Table 2) [27]. We did not repeat Eicher’s work, but
extended it by reacting the electron rich dihydroisoquinoline based
cyclic ketimines 56a-d (Table 2) with cyclopropenones 38e40 in
a
Compounds 55a-55d were reported by Eicher [27] and were not synthesized as
part of our work (see text).
b
These five compounds were synthesized as part of our work.
Compound 57ai was also reported by Cui (63% yield) during the course of our
c
work [40].
d
Compounds 57e-57h were recently reported by Cui [40] and were not syn-
thesized as part of our work (see text).
acetonitrile or chloroform as solvent and obtained the expected
pyrroloisoquinolines 57ai/ii-d (Table 2). The dihydroisoquinoline
56a [37] was prepared by a standard Bischler-Napieralski reaction,
whereas the fluorinated analogues 56b and 56c [37] required the
use of Movassaghi and Hill’s [38] modified procedure using tri-
fluoromethanesulfonic anhydride in the presence of 2-
chloropyridine. The dihydroisoquinoline 56d was prepared from
the reaction of methyl eugenol with acetonitrile [39], and gave the
product 57d as a 2:5 mixture of diastereoisomers. We did not
determine which was the major diastereoisomer. During the
preparation of this manuscript, the group of Cui [40] reported the
synthesis of pyrroloisoquinoline 57ai in 63% yield from the reaction
of imine 56a with diphenylcyclopropenone in DCE as solvent, and
also reported the formation of pyrroloisoquinolines 57e-h in high
yields from the reaction of electron rich dihydroisoquinolines 56e-
h and diphenylcyclopropenone, also shown in Table 2 [40]. The
reactions and literature observations shown in Table 2 confirm that
cyclic ketimines react in the expected manner with cyclo-
propenones to give fused pyrrolidinones with no competing
Scheme 5. Proposed Mechanism for Bridgehead Oxidation.

F. Jamshaid et al. / Tetrahedron 76 (2020) 131570
5
oxidations. We have shown previously that cyclic imidates and
thioimidates [21,35] also react to give the expected products, a
process was recently exploited by Nahkla and Wood [41] who used
an imidate-cyclopropenone addition process as a key step in their
synthesis of aspergilline A.
We next used a known Bischler-Napieralski reaction of trypt-
amine to produce the dihydropyrido[3,4-b]indole 58 [42] (Scheme
7), hence targeting the indolizinoindole nucleus after reaction with
cyclopropenones. The indolizinoindole nucleus is an attractive
target and is present in natural products such as harmicine 8
(Fig. 1). The reaction of compound 58 with diphenylcycloprope-
none resulted in a pure product precipitating from the solution,
which was found to be the unexpected dimeric species 59a
(Scheme 7) formed in 27% yield. The structure of dimer 59a was
inferred by HRMS, and confirmed by X-ray crystallographic analysis
(Fig. 2) [43]. Chromatographic purification of the remaining com-
plex mixture gave a further 6% of compound 59a together with a
13% yield of a second product, tentatively identified as the azoni-
noindole 60 on the basis of spectroscopic analysis. Compound 60
was formed as an inseparable mixture in ~95% purity with minor
amounts (~5%) of other tautomers. Compound 58 reacted in a
similar fashion with bis(4-fluorophenyl)cyclopropenone 40 to give
the dimeric species 59b, which again precipitated out from the
solution in pure form (19% yield). The formation of the dimers 59a/
b is consistent with the pathway suggested in Scheme 5, above,
whereby an initial reaction to give the pyrrolidinone 61 (Scheme 7)
Fig. 2. X-ray structure of compound 59a.
is followed by the formation of the stabilized captodative radical 62.
Dimerization would then give species 59a and 59b. The dimeriza-
tion of captodative radicals is precedented [26], and it is interesting
that radical 62 was able to dimerize, whereas such a process was
not observed with the non-indole species that are discussed above
(Scheme 5) and in our previous studies [22]. It is possible that the
formation of the dimer is driven by the stabilization offered by the
hydrogen bonding seen in the crystal structure of dimer 59a, or that
the different stabilization options that are present in radical 62
direct the reaction down a different pathway. The product tenta-
tively identified as compound 60 had data that showed it had
gained an extra oxygen atom and had lost two hydrogen atoms
(HRMS). It also clearly showed two carbonyl groups and a non-
aromatic/non-vinylic CH in the 13C NMR data, and lacked any evi-
dence of the bridgehead CeOH characteristic of the (now expected)
bridgehead-hydroxy compound 63. We propose that the radical 62
picks up oxygen to give the hydroxy intermediate 63, consistent
with previous observations, but that the aminol functionality un-
dergoes ring opening to give the azoninoindole nucleus 64, which
after loss of hydrogen and tautomerism could form the proposed
final azoninoindole 60.
In order to understand more about how other dihydropyrido
[3,4-b]indoles might react, we also explored the use of a cyclic
ketimine system, choosing in this case the substituted dihy-
dropyrido[3,4-b]indole (dihydro-b-carboline) systems 65 and 66, as
shown in Scheme 8. Precursors 65 and 66 were easily synthesized
[44] by reacting tryptamine with either succinic anhydride or
glutaric anhydride in the presence of methanol to give the esters 67
and 68 (Scheme 8) which then underwent Bischler-Napieralski ring
closure to give the desired dihydropyrido[3,4-b]indoles 65 and 66
[44]. Reaction with diarylcyclopropenones then gave the expected
indolizinoindoles 69, 70 and 71 in 74e81% yield, showing that the
cyclic ketimines 65 and 66 behaved perfectly as reaction partners,
being unable to form a free-radical at the bridgehead and hence
unable to undergo bridgehead oxidation to the hydroxy compound,
dimerization or radical extrusion of hydrogen. We had hoped that
the side-chain ester present in products 69e71 would allow the
formation of an additional ring to give pentacyclic systems, but
have so far found this to be unachievable. It is of note that, whilst
Scheme 7. Reactivity of Dihydropyrido[3,4-b]indole 58 Reagents and Conditions: (a)
38 or 40, MeCN, RT, 16 h.

6
F. Jamshaid et al. / Tetrahedron 76 (2020) 131570
4. Acknowledgements
We acknowledge the University of Huddersfield for financial
support. Thanks are due to Dr Neil McLay and Dr Jack Blackburn of
the University of Huddersfield for NMR and mass spectral data
collection.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2020.131570.
5. Experimental
Reagents, solvents and anhydrous solvents were purchased
from Fischer Scientific, Acros Organics, Sigma-Aldrich, VWR,
Manchester Organics, Fluorochem and Alfa-Aesar, and were used as
supplied. Methyl eugenol was a gift from Citrefine International
Limited. Reactions were monitored on Merck TLC silica gel 60 F254
aluminium sheets. Visualisation of spots was accomplished using a
UV lamp (254 or 365 nm). Column chromatography was performed
on silica gel (Aldrich, technical grade, pore size 60 Å, 40e63 mm
particle size). Nuclear magnetic resonance (NMR) spectra were
recorded on Bruker Ascend 400 (400 MHz e 1H, and 100 MHze13C),
Bruker Fourier 300 (300 MHz e 1H, and 75 MHze13C), Bruker
Avance 500 (500 MHz e 1H, and 125 MHze13C) or Bruker Avance
600 (600 MHz e 1H, and 150 MHze13C) spectrometers using CDCl3,
(CD3)2SO, (CD3)2CO, CD3OD or D2O as solvent and as internal
Scheme 8. The Synthesis of Indolizinoindoles.
standard. The chemical shifts (d) are expressed in parts per million
(ppm). Mass spectra were recorded on Agilent 6210 TOF MS (Dual
ESI source), Agilent 6530 Q-TOF MS (Jet Stream ESI source), Agilent
1290 HPLC þ 6530 Q-TOF (Dual AJSESI source þ ve) or Agilent
7890A-5975C (EI-GCMS) and spectra were recorded in positive
mode. FT-IR spectra were recorded on a Thermo Nicolet 380 FT-IR
Spectrometer with Diamond ATR (neat sample). Melting points
were recorded using a Stuart SMP10 melting point apparatus.
Compounds 29 [30], 30 [30], 35 [33], 37 [34], and 65e67 [44], were
synthesized by modified literature methods, procedures for which
can be found in the supplementary information, together with
NMR spectra of previously unreported compounds.
Scheme 9. Cui’s Recently Reported Synthesis of Indolizinoindoles [40].
we were preparing this manuscript, Cui reported that aryl
substituted dihydro- -carbolines 72 (cyclic ketimines) react with
b
cyclopropenones 38 and 39 to give the expected indolizinoindoles
in excellent yields, shown in Scheme 940
3. Conclusions
5.1. Generation of (3aR,7S,7aR)-7-(benzyloxy)-2,2-dimethyl-
3a,6,7,7a-tetrahydro-[1,3]dioxolo[4,5-c]pyridine (24)
During an attempted synthesis of castanospermine, using the
addition of a cyclopropenone to a cyclic aldimine as the key step,
we observed the installation of an additional OH at the carbon
bridgehead of a precursor bicyclic indolizidinone system. We have
previously observed the same phenomenon whilst attempting the
synthesis of other indolizidines and pyrrolizidines using the
equivalent key step. Dihydroisoquinolines that were unsubstituted
at the imine carbon behaved in the same manner to give pyrro-
loisoquinolines with a hydroxy group on the carbon bridgehead,
whereas dihydroisoquinolines that were substituted at the imine
carbon gave the expected pyrroloisoquinolines. Dihydropyrido[3,4-
b]indoles that were unsubstituted on the imine carbon reacted
with cyclopropenones to give a dimeric indolizinoindole, whereas
dihydropyrido[3,4-b]indoles which were substituted at the imine
carbon reacted with cyclopropenones to give the expected
indolizinoindoles.
In an oven dried three neck RBF, the azido aldehyde 23 [28]
(140 mg, 0.459 mmol) was dissolved in dry THF (10 mL) under an
atmosphere of nitrogen. Activated powdered 4 Å molecular sieves
(100 mg) were added and the mixture was stirred at room tem-
perature for 15 min PPh3 (121 mg, 0.461 mmol) in dry THF (2 mL)
was added via syringe and the mixture was stirred until TLC
showed complete loss of the azide (15 min). Attempts to isolate the
intermediate iminophosphorane were unsuccessful. The reaction
vessel was transferred into an oil bath, and the mixture was stirred
at 55 ꢀC for 5 h, at which point analysis by IR spectroscopy indicated
that the aldehyde had disappeared. Attempts to purify the product
resulted in its decomposition (see main text).
5.2. Synthesis of (3R,4S,5S)-3,4,5-tris(benzyloxy)-2,3,4,5-
tetrahydropyridine 1- oxide (31) [31]
Declaration of competing interest
To the mesylate (30) [29] (2.30 g, 3.06 mmol) dissolved in THF
(30 mL), was added 4 Å molecular sieves (2 g), followed by TBAF
(3.36 mL, 1 M solution in THF, 3.36 mmol). The mixture was heated
at reflux for 30 min, concentrated under vacuum, and purified by
chromatography over silica (MeOH/EtOAc, 5:95), to afford the
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.

F. Jamshaid et al. / Tetrahedron 76 (2020) 131570
7
nitrone (31) (900 mg, 70% yield). 1H NMR (400 MHz, CDCl3)
d:
3256, 1657, 1601, 1542, 1427, 1350, 1121, 1074, 973, 791, 767, 720,
527; HRMS: [Mþ] for C24H19NO2 calculated 353.1416, found
353.1420.
7.37e7.26 (15H, m, 3 ꢁ C6H5), 6.88 (1H, br, s, CH]N), 4.66e4.50
(7H, m, CH þ 3 ꢁ CH2), 4.38e4.37 (1H, m, CH), 4.06e4.00 (2H, m,
2 ꢁ CH), 3.76 (1H, dd, J ¼ 8.5, 2.7 Hz, CH). 13C NMR (100 MHz, CDCl3)
d: 137.7 (CH]N), 137.2 (qC), 137.1 (qC), 132.8 (qC), 128.63 (CH),
5.5. Synthesis of 10b-hydroxy-2,3-bis(dimethoxyphenyl)-5,6-
128.58 (CH), 128.4 (CH), 128.19 (CH), 128.16 (CH), 128.0 (CH), 127.9
(CH), 127.8 (CH), 127.7 (CH), 82.8 (CH), 80.4 (CH), 77.5 (CH), 73.5
(CH2), 71.9 (CH2), 71.7 (CH2), 66.1 (CH2). Consistent with the liter-
ature data for this compound [31].
dihydropyrrolo[2,1-a]isoquinolin-1-one (42)
To a stirred solution of 3,4-dihydroisoquinoline [33] (0.024 g,
0.182 mmol) in CDCl3 (5 mL), was added 2,3-bis(4-methoxyphenyl)
cycloprop-2-en-1-one [35,36] (0.050 g, 0.186 mmol) at room tem-
perature under an air atmosphere. The reaction mixture was stirred
at room temperature for 3 h and then solvents were removed by
rotary evaporation. The crude product was purified by flash silica
chromatography to afford the title compound in ~90% purity as an
orange yellow solid (0.040 g, 52% yield), m.p. 86e87 ꢀC. Rf 0.37
5.3. Synthesis of (6R,7S,8R)-6,7,8-tris(benzyloxy)-8a-hydroxy-
6,7,8,8a-tetrahydroindolizin-1(5H)-one (33)
To a solution of nitrone (31) (350 mg, 0.838 mmol) in dry THF
(20 mL) was added n-tributylphosphine (419 ml, 1.696 mmol), and
the solution was stirred at 65 ꢀC for 48 h. The solvent was removed
by rotary evaporation, and the residue was purified by column
chromatography on silica with 1% MeOH in ethyl acetate to afford
the imine (32) (198 mg, 59% yield) as an unstable oily mass, which
was used immediately. A small sample (25 mg) was removed for
analysis, but degraded. To a solution of the imine (32) (173 mg,
0.431 mmol) in acetonitrile (15 mL), cooled to ꢂ10 ꢀC, was added
cyclopropenone (70 mg, 1.295 mmol) generated in-situ from the
acetal [29,35], in acetone (5 mL), dropwise over a period of 10 min.
The solution was allowed to warm to room temperature over 3 h
and then stirred overnight at room temperature. The reaction mass
was concentrated by rotary evaporation under vacuum and the
crude residue was purified using silica column chromatography to
give the product (87 mg, 43% yield, ~95% single diastereoisomer) as
a pale yellow oil. Rf 0.3 (ethyl acetate/petroleum ether, 3:7); 1H
(ethyl acetate/petroleum ether, 1:5); 1H NMR (400 MHz, CDCl3)
d:
8.13 (1H, d, J ¼ 8.0 Hz, Ar), 7.39e7.26 (5H, m, Ar), 7.07 (1H, d,
J ¼ 7.2 Hz, Ar), 6.96e6.91 (3H, m, Ar), 6.67 (2H, d, J ¼ 8.7 Hz, Ar),
3.97e3.55 (3H, m, CH2 & OH), 3.86 (3H, s, OCH3), 3.72 (3H, s, OCH3),
2.68e2.43 (2H, m, CH2); 13C NMR (100 MHz, CDCl3)
d: 198.3 (C]O),
173.5 (qC), 161.4 (qC), 157.7 (qC), 134.0 (qC), 133.6 (qC), 130.5 (CH),
130.1 (CH), 128.7 (CH), 128.4 (CH), 128.1 (CH), 127.4 (CH), 123.4 (qC),
122.4 (qC), 114.5 (CH), 113.4 (CH), 112.9 (qC), 85.8 (qC), 55.4 (OCH3),
55.1 (OCH3), 40.9 (CH2), 28.1 (CH2); IR (neat, cmꢂ1
) ymax: 3341, 1668,
1604, 1518, 1456, 1289, 1243, 1173, 1110, 1024, 832, 747, 581, 531;
HRMS: [Mþ] for C26H23NO4 calculated 413.1627, found 413.1627.
5.6. Synthesis of 10b-hydroxy-2,3-bis(difluorophenyl)-5,6-
dihydropyrrolo[2,1-a]isoquinolin-1-one (43)
NMR (500 MHz, CDCl3)
d
: 7.77 (1H, d, J ¼ 3.7 Hz, NCH]CH),
To a solution of 3,4-dihydroisoquinoline [33] (0.027 g,
7.39e7.18 (15H, m, 3 ꢁ C6H5), 5.23 (1H, d, J ¼ 3.7 Hz, NCH]CHC]
O), 4.98 (1H, d, J ¼ 11.7 Hz, CHH), 4.67 (1H, d, J ¼ 11.7 Hz, CHH), 4.62
(1H, d, J ¼ 11.7 Hz, CHH), 4.49e4.57 (4H, m, 4 ꢁ CH), 4.19 (1H, dd,
J ¼ 6.8 and 5.8 Hz, CH), 4.0 (1H, bs, OH), 3.82 (1H, d, J ¼ 6.8 Hz, CH),
3.59 (1H, dd, J ¼ 9.4 and 4.9 Hz, CH), 3.54 (1H, dd, J ¼ 9.4 and 7.2 Hz,
CH), 3.46 (1H, ddd, J ¼ 9.4, 5.8 and 4.9 Hz, CH). 13C NMR (125.7 MHz,
0.206 mmol) in acetonitile (10 mL) was added 2,3-bis(4-
fluorophenyl)cycloprop-2-en-1-one [36] (0.050 g, 0.205 mmol).
The solution was stirred at room temperature for 48 h. The aceto-
nitrile was removed under vacuum and the crude product was
purified via silica column chromatography to afford the title com-
pound in ~95% purity as a bright yellow solid (0.028 g, 36% yield),
m.p. 134e139 ꢀC. Rf 0.28 (ethyl acetate/petroleum ether, 3:7); 1H
CDCl3) d: 202.2 (qC, C]O), 169.2 (CH]CH), 137.6 (qC), 137.5 (qC),
137.0 (qC), 128.6 (CH), 128.5 (CH), 128.41 (CH), 128.40 (CH), 128.1
(CH), 127.92 (CH), 127.85 (CH), 127.8 (CH), 127.7 (CH), 102.5 (CH]
CH), 92.4 (qC-OH), 87.4 (CH), 82.3 (CH), 73.6 (CH2), 73.3 (CH2), 72.8
NMR (600 MHz, CDCl3)
d
: 8.11 (1H, d, J ¼ 7.9 Hz, Ar), 7.39e7.08 (7H,
m, Ar), 6.92e6.90 (2H, m, Ar), 6.82e6.79 (2H, m, Ar), 4.52e3.80 (1H,
bs, OH), 3.83 (1H, ddd, J ¼ 2.1, 5.0, 13.9 Hz, CHH), 3.63 (1H, ddd,
J ¼ 4.3,11.7,13.9 Hz, CHH), 2.64e2.59 (m, 2H, m, CH2); 19F (376 MHz,
(CH2), 71.9 (CH2), 63.1 (CH). IR (neat, cmꢂ1
) ymax: 3377 (br, OH),
3064, 3031, 2927, 2871, 1693 (C]O), 1538, 1454, 1114, 735. HRMS:
CDCl3)
CDCl3)
d
: ꢂ107.9 (m, ArF), ꢂ115.8 (m, ArF); 13C NMR (150 MHz,
[M þ Naþ] for C29H29NNaO5 calculated 494.1937, found 494.1948..
d: 198.1 (C]O), 172.8 (qC), 164.0 (d, J ¼ 251 Hz, qCꢂF), 161.2
(d, J ¼ 244 Hz, qCꢂF), 133.9 (qC), 133.2 (qC), 130.4 (d, J ¼ 7.8 Hz,
CHm-F) 128.6 (d, J ¼ 8.7 Hz, CHm-F), 128.3 (CH), 127.6 (CH), 126.5 (d,
J ¼ 3.3 Hz, qCp-F), 126.1 (d, J ¼ 3.5 Hz, qCp-F), 116.7 (d, J ¼ 21.8 Hz,
CHo-CF), 115.0 (d, J ¼ 21.2 Hz, CHo-CF), 112.7 (qC), 85.8 (qC), 40.7
5.4. Synthesis of 10b-hydroxy-2,3-diphenyl-5,6-dihydropyrrolo
[2,1-a]isoquinolin-1-one (41)
To a stirred solution of 3,4-dihydroisoquinoline [33] (0.030 g,
0.230 mmol) in MeCN (5 mL), was added diphenylcyclopropenone
(0.050 g, 0.242 mmol) at room temperature under an air atmo-
sphere. The reaction mixture was stirred at room temperature for
3 h and then solvents were removed by rotary evaporation. The
crude product was purified by flash silica chromatography to afford
the title compound as an orange yellow solid (0.051 g, 59% yield),
m.p. 169e170 ꢀC. Rf 0.42 (ethyl acetate/hexane, 1:1); 1H NMR
(CH2), 29.3 (CH2); IR (neat, cmꢂ1
) ymax: 3284, 2920, 1657, 1551, 1495,
1346, 1230, 1155, 1072, 974, 831, 752, 569, 522; HRMS: [M þ Hþ] for
C24H18NO2F2 calculated 390.1304, found 390.1301.
5.7. Synthesis of 8,9-dimethoxy-10b-hydroxy-2,3-diphenyl-5,6-
dihydropyrrolo[2,1-a]isoquinolin-1-one (44)
To a stirred solution of 6,7-dimethoxy-3,4-dihydroisoquinoline
[34] (0.09 g, 0.48 mmol) in chloroform (5 mL), was added diphe-
nylcyclopropenone (0.10 g, 0.48 mmol) at room temperature under
an air atmosphere. The reaction mixture was stirred for 3 h and
then the solvent was removed by rotary evaporation. The crude
product was purified by flash chromatography affording the title
compound as an orange yellow solid (0.13 g, 65% yield), m.p.
154e156 ꢀC. Rf 0.30 (ethyl acetate/hexane, 1:1); 1H NMR (400 MHz,
(400 MHz, CDCl3)
d
: 8.14 (1H, d, J ¼ 7.8 Hz, Ar), 7.53e7.34 (5H, m,
Ar), 7.30 (2H, dd, J ¼ 7.5 and 7.5 Hz, Ar), 7.07e7.03 (4H, m, Ar), 6.98
(2H, dd, J ¼ 7.6 and 1.5 Hz, Ar), 3.88 (2H, bs and ddd, J ¼ 13.8, 5.2 and
1.7 Hz, CHH and OH), 3.62 (1H, ddd, J ¼ 12.2, 12.2 and 3.7 Hz, CHH),
2.72e2.63 (1H, m, CHH), 2.57 (1H, bd, J ¼ 14.8 Hz, CHH); 13C NMR
(100 MHz, CDCl3) d: 198.2 (C]O), 174.2 (qC), 134.0 (qC), 133.3 (qC),
130.8 (CH), 130.6 (qC), 130.4 (qC), 129.2 (CH), 128.8 (CH), 128.60
(CH), 128.56 (CH), 128.3 (CH), 127.9 (CH), 127.5 (CH), 126.0 (CH),
CDCl3)
d: 7.64 (1H, s, Ar), 7.51e7.46 (5H, m, Ar), 7.12e7.01 (3H, m,
113.4 (qC), 85.7 (qC), 40.7 (CH2), 29.3 (CH2); IR (neat, cmꢂ1
) ymax:
Ar), 7.00 (2H, d, J ¼ 7.5 Hz, Ar), 6.54 (1H, s, Ar), 4.00 (3H, s, OCH3),

8
F. Jamshaid et al. / Tetrahedron 76 (2020) 131570
3.86 (3H, s, OCH3), 3.89e3.81 (1H, m, CHH), 3.60 (2H, m, CHH &
OH), 2.65e2.57 (1H, m, CHH), 2.47 (1H, bd, J ¼ 14.0 Hz, CHH); 13C
(0.0377 g, 0.1836 mmol) diphenylcyclopropenone (0.0250 g,
0.1212 mmol) were dissolved in acetonitrile (5 mL). The flask
heated at 82 ꢀC for 1 h, while continuously stirring. After heating,
the solvent was removed in vacuo. The crude product was purified
by silica column chromatography to give the product as a pale
yellow solid (0.0296 g, 57% yield), m.p. 235e237 ꢀC. Rf 0.3 (ethyl
NMR (100 MHz, CDCl3) d: 198.1 (C]O), 173.8 (qC), 149.4 (qC), 148.5
(qC), 130.69 (CH), 130.66 (qC), 130.5 (qC), 129.8 (CH), 129.2 (CH),
128.8 (CH), 127.9 (CH), 126.6 (qC), 126.0 (CH), 124.9 (qC), 113.2 (qC),
110.3 (CH), 110.3 (CH), 85.4 (qC), 56.2 (CH3), 55.9 (CH3), 40.7 (CH2),
28.9 (CH2); IR (neat, cmꢂ1
)
ymax: 3250.1, 2921.1, 2852.2, 1643.7,
1446.6, 1360.1, 1257.0, 1223.2, 1124.7, 1037.7; HRMS: [Mþ] for
26H23NO4 calculated 413.1627, found 413.1617.
acetate/hexane, 4:6); 1H NMR (300 MHz, CDCl3)
d: 7.59 (1H, s, Ar),
7.49e7.28 (5H, m, Ph), 7.10e7.06 (4H, m, Ph), 7.04e7.01 (1H, m, Ph),
6.52 (1H, s, Ar), 4.00 (3H, s, OMe), 3.92 (1H, dd, J ¼ 10.2, 3.5 Hz,
CHH), 3.84 (3H, s, OMe), 3.46 (1H, ddd, J ¼ 10.2, 10.2, 2.7 Hz, CHH),
2.74e2.56 (1H, m, CHH), 2.49 (1H, dd, J ¼ 11.9,1.7 Hz, CHH),1.76 (3H,
C
5.8. Synthesis of 8,9-dimethoxy-10b-hydroxy-2,3-bis(4-
methoxyphenyl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-1-one (45)
s, Me); 13C NMR (75 MHz, CDCl3)
d: 199.5 (C]O), 172.3 (qC), 148.2
(qC), 147.9 (qC), 131.7 (qC), 130.9 (qC), 130.2 (CH), 129.1 (CH), 128.7
(CH), 128.4 (qC), 128.2 (CH), 127.7 (CH), 125.3 (CH), 124.3 (qC), 113.4
(qC),110.6 (CH),109.6 (CH), 67.9 (qC), 56.2 (OCH3), 55.9 (OCH3), 40.7
To a stirred solution of 6,7-dimethoxy-3,4-dihydroisoquinoline
[33] (0.15 g, 0.78 mmol) in chloroform (5 mL), was added 2,3-
bis(4-methoxyphenyl)cycloprop-2-en-1-one [35,36] (0.21 g,
0.78 mmol) at room temperature under an air atmosphere. The
reaction mixture was stirred at room temperature for 3 h and then
solvents were removed by rotary evaporation. The crude product
was purified by silica chromatography to afford the title compound
as an orange yellow solid (0.16 g, 69% yield), m.p. 142e143 ꢀC. Rf
(CH2), 29.8 (CH2), 26.4 (CH3). IR (neat, cmꢂ1
) ymax: 2937.2, 2835.0,
2360.6, 2339.3, 1656.6, 1602.6, 1544.8, 1504.3, 1432.9, 1404.0,
1344.2, 1324.9, 1259.4, 1230.4, 1207.3, 1124.4, 1080.0, 999.0, 773.4,
732.90, 690.4, 640.3, 551.6. HRMS: [M þ Hþ] for C27H26NO3,
calculated 412.1917, found 412.1913.
0.25 (ethyl acetate/hexane, 2:1); 1H NMR (400 MHz, DMSO-d6)
d:
5.11. Synthesis of 8,9-Dimethoxy-10b-methyl-2,3-bis(4-
dimethoxyphenyl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-1-one
(57aii)
7.49 (1H, s, Ar), 7.29 (2H, bd, J ¼ 8.5 Hz, Ar), 7.06 (2H, d, J ¼ 7.7 Hz,
Ar), 6.84 (2H, d, J ¼ 8.0 Hz, Ar), 6.68 (2H, d, J ¼ 8.5 Hz, Ar), 6.65 (1H,
s, Ar), 3.81 (3H, s, CH3), 3.78 (3H, s, CH3), 3.71 (3H, s, CH3), 3.64 (3H,
s, CH3), 3.50e3.29* (3H, m, OH and CH2), 2.40e2.20* (2H, m, CH2);
6,7-Dimethoxy-1-methyl-3,4-dihydroisoquinoline [37] (0.029 g,
0.141 mmol) and 2,3-bis(4-methoxyphenyl)cycloprop-2-en-1-one
[35,36] (0.025 g, 0.094 mmol) were dissolved in a mixture of
acetonitrile (2.5 mL) and chloroform (7.5 mL). The solution was
heated at reflux for 96 h, with continuous stirring. The solvent was
removed and the crude product was purified via silica column
chromatography to give the product as a bright yellow solid
(0.024 g, 53% yield), m.p. 235e237 ꢀC. Rf 0.3 (ethyl acetate/hexane,
13C NMR (100 MHz, CDCl3)
d: 197.7 (C]O), 172.6 (qC), 161.1 (CH),
157.4 (qC), 149.1 (qC), 147.9 (qC), 130.6 (qC), 129.9 (CH), 127.2 (qC),
126.6 (qC), 124.4 (qC), 122.9 (qC), 115.1 (CH), 113.6 (CH), 111.9 (CH),
111.4 (qC), 111.2 (CH), 85.5 (qC), 56.0 (OCH3), 55.9 (OCH3), 55.8
(OCH3), 55.3 (OCH3), 40.5* (CH2), 28.8 (CH2); IR (neat, cmꢂ1
) ymax:
3318, 1644, 1604, 1517, 2492, 1337, 1248, 1172, 1113, 1014, 1001, 828,
725, 583, 561, 540, 528; HRMS: [Mþ] for C28H27NO6 calculated
473.1838, found 473.1837. (* signal overlaps with DMSO/H2O signal
from solvent).
11:9); 1H NMR (400 MHz, CDCl3)
d: 7.57 (s, 1H, Ar), 7.37e7.36 (2H,
m, Ar), 7.01 (2H, d, J ¼ 8.6 Hz, Ar), 6.96 (2H, d, J ¼ 7.6 Hz, Ar), 6.68
(2H, d, J ¼ 8.6 Hz, Ar), 6.50 (1H, s, Ar), 4.00 (3H, s, OMe), 3.95 (1H,
overlapping m, CHH), 3.86 (3H, s, OMe), 3.82 (3H, s, OMe), 3.72 (3H,
s, OMe), 3.47e3.40 (1H, m, CHH), 2.61 (1H, m, CHH), 2.46 (1H, d,
5.9. Synthesis of 8,9-dimethoxy-10b-hydroxy-2,3-bis(4-
fluorophenyl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-1-one (46)
J ¼ 14.4 Hz, CHH), 1.74 (3H, s, Me); 13C NMR (100 MHz, CDCl3)
d:
To a stirred solution of 6,7-dimethoxy-3,4-dihydroisoquinoline
[34] (0.096 g, 0.499 mmol) in chloroform (5 mL), was added 2,3-
199.6 (C]O), 171.7 (qC), 160.9 (qC), 157.2 (qC), 148.1 (qC), 147.8 (qC),
129.7 (2 ꢁ CH), 128.4 (qC), 124.5 (qC), 124.4 (qC), 122.9 (qC), 114.5
(CH), 113.2 (CH), 113.1 (qC), 110.5 (CH), 109.7 (CH), 67.8 (qC), 56.1
(OCH3), 55.8 (OCH3), 55.4 (OCH3), 55.1 (OCH3), 40.8 (CH2), 29.7
bis(4-fluorophenyl)cycloprop-2-en-1-one
[36]
(0.121
g,
0.497 mmol) at room temperature under an air atmosphere. The
reaction mixture was stirred at room temperature for 3 h and then
solvents were removed by rotary evaporation. The crude product
was purified by silica chromatography to afford the title compound
as a pale green oil (0.075 g, 34% yield). Rf 0.3 (CH2Cl2/MeOH, 5:1);
(CH2), 26.3 (CH3); IR (neat, cmꢂ1
) ymax: 2929.5, 2833.1, 1652.8,
1515.9, 1459.9, 1404.0, 1342.3, 1299.9, 1247.8, 1174.5, 1022.1, 919.9,
829.3, 582.4, 549.6; HRMS: [M þ Hþ] for C29H30NO5, calculated
472.2126, found 472.2119.
1H NMR (600 MHz, CDCl3)
d: 7.63 (1H, s, Ar), 7.41 (2H, bs, Ar), 7.19
(2H, bs, Ar), 6.95e6.97 (2H, m, Ar), 6.84e6.87 (2H, m, Ar), 6.56 (1H,
s, Ar), 4.00 (3H, s, OCH3), 3.85e3.98 (2H, s, OH þ CHH), 3.88 (3H, s,
OCH3), 3.60e3.66 (1H, m, CHH), 2.57e2.61 (1H, m, CHH), 2.50e2.53
5.12. Synthesis of 10b-(Difluoromethyl)-8,9-dimethoxy-2,3-
diphenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-1-one (57b)
(1H, m, CHH); 13C NMR (150 MHz, CDCl3)
d
: 198.0 (C]O),172.4 (qC),
1-(Difluoromethyl)-6,7-dimethoxy-3,4-dihydroisoquinoline
[37] (0.035 g, 0.145 mmol) and diphenylcyclopropenone (0.025 g,
0.127 mmol) were dissolved in a mixture acetonitrile (5 mL) and
chloroform (4 mL). The reaction mixture was heated at reflux, with
continuous stirring, for 48 h. The mixture was cooled, the solvent
was removed by rotary evaporation and the crude material was
purified by silica column chromatography. The product was ob-
tained as a yellow solid (0.023 g, 41% yield), m.p. 234e238 ꢀC. Rf
163.0 (d, J ¼ 251.1 Hz, qCꢂF), 161.2 (d, J ¼ 244.3 Hz, qCꢂF), 149.5
(qC), 148.6 (qC), 130.4 (2C, d, J ¼ 7.8 Hz, 2 ꢁ CHm-F), 126.49 (qC),
126.45 (bs, qCp-F), 126.2 (d, J ¼ 3.4 Hz, qCp-F), 124.8 (qC), 116.7 (d,
J ¼ 21.8 Hz, CHo-F),115.0 (d, J ¼ 21.2 Hz, CHo-F),112.6 (qC),110.3 (2C,
2 ꢁ CH), 85.5 (qCOH), 56.2 (OCH3), 55.9 (OCH3), 40.8 (CH2), 21.8
(CH2); IR (neat, cmꢂ1
) ymax: 3460.4, 2928.0, 2853.3, 2117.0, 1677.6,
1513.9, 1265.8, 1226.0, 1154.9, 1132.2; HRMS: [M þ Hþ] for
C
26H22F2NO4 calculated 450.1518, found 450.1509.
0.33 (ethyl acetate/hexane, 4:6); 1H NMR (300 MHz, CDCl3)
d: 7.62
(1H, s, Ar), 7.52e7.30 (5H, m, Ph), 7.16e7.03 (5H, m, Ph), 6.62 (1H, s,
Ar), 6.35 (1H, t, J ¼ 54 Hz, CHF2), 4.03 (3H, s, OMe), 3.90e4.01 (1H,
m, CHH), 3.88 (3H, s, OMe), 3.75e3.63 (1H, m, CHH), 2.73e2.53 (2H,
5.10. Synthesis of 8,9-Dimethoxy-10b-methyl-2,3-diphenyl-5,6-
dihydropyrrolo [2,1-a]isoquinolin-1-one (57ai)
m, CH2). 13C NMR (75 MHz, CDCl3)
d: 194.0 (C]O), 176.3 (qC), 148.9
6,7-Dimethoxy-1-methyl-3,4-dihydroisoquinoline
[37]
(qC), 148.4 (qC), 130.8 (qC), 130.7 (CH), 130.2 (qC), 129.2 (CH), 128.8

F. Jamshaid et al. / Tetrahedron 76 (2020) 131570
9
(bs, qC), 128.5 (CH), 128.2 (CH), 127.9 (CH), 126.3 (qC), 125.9 (CH),
5.15. Synthesis of 2,2ʹ,3,3ʹ-tetraphenyl-6,6ʹ,11,11ʹ-tetrahydro-
[11b,11bʹ-bis(indolozino[8,7-b]indole)]-1,1ʹ-one (59a) and 4,5-
diphenyl-5,8-dihydroazonino[5,4-b]indole-6,7-dione (60)
117.0 (t, J ¼ 245 Hz, CHF2), 115.6 (qC), 111.2 (CH), 108.5 (CH), 70.0 (t,
J ¼ 18.5 Hz, qCCHF2), 56.2 (OCH3), 55.9 (OCH3), 42.4 (CH2), 29.0
(CH2); IR (neat, cmꢂ1
) ymax: 2920, 2850, 1666, 1520, 1319, 1261,
1065, 1007, 876, 800, 735, 696, 542; HRMS: [M þ Hþ] for
To a stirred solution of dihydropyrido[3,4-b]indole (58) [42]
(0.086 g, 0.505 mmol) in acetonitrile (5 mL) was added diphe-
nylcyclopropenone (0.086 g, 0.417 mmol) in one portion. The bright
yellow solution was stirred at room temperature and monitored by
TLC. After 4 h, a precipitate was formed, and the mixture was
filtered. The precipitate (0.043 g, 27%) was found to be the bis(in-
dolizino[8,7-b]indolone 59a. The solution was concentrated by
rotary evaporation and purified by column chromatography on
silica to give an additional amount of the dimeric species (0.010 g,
6%). Also recovered from the mixture was a second product
(0.021 g, 13%) tentatively identified as the azoninoindole 60, and
isolated in ~95% purity.
C
29H24F2NO3, calculated 448.1725, found 448.1716.
5.13. Synthesis of 10b-(Fluoromethyl)-8,9-dimethoxy-2,3-bis(4-
fluorophenyl)-5,6-dihydropyrrolo[2,1-a]isoquinolin-1-one (57c)
1-(Fluoromethyl)-6,7-dimethoxy-3,4-dihydroisoquinoline [37]
(0.113 g, 0.506 mmol) and bis(4-difluorophenyl)cyclopropenone
[36] (0.121 g, 0.495 mmol) were dissolved in chloroform (5 mL). The
reaction mixture was stirred at room temperature for 3 h. The
solvent was removed by rotary evaporation and the crude material
was purified by silica column chromatography. The product was
obtained as a light brown oil (0.063 g, 27% yield). Rf 0.28 (ethyl
Bis(indolizino[8,7-b]indolone 59a: 1H NMR (400 MHz, CDCl3)
d:
9.22 (2H, bs, NH), 7.53e7.40 (10H, m, Ar), 7.30e7.24 (4H, m, Ar),
7.20e7.08 (14H, m, Ar), 3.98 (2H, app d, J ¼ 8.6 Hz, NCHH), 3.49 (2H,
bm, NCHH), 2.74 (2H, app d, J ¼ 14.4 Hz, CHH), 2.64e2.55 (2H, m,
acetate/hexane, 5:5). 1H NMR (400 MHz, CDCl3)
d: 7.56 (1H, s, Ar),
7.55e7.26 (2H, bm, Ph), 7.19e7.15 (2H, m, Ph), 7.01e6.98 (2H, m, Ar),
6.84e6.80 (2H, m, Ar), 6.58 (1H, s, Ar), 6.35 (2H, d, J ¼ 47.5 Hz,
CH2F), 4.00 (3H, s, OMe), 3.97e3.87 (1H, m, CHH), 3.85 (3H, s, OMe),
3.65e3.58 (1H, m, CHH), 2.67e2.60 (1H, m, CHH), 2.55 (1H, dd,
CHH); 13C NMR (100 MHz, CDCl3)
d: 195.1 (qC), 174.5 (qC), 136.8
(qC), 130.9 (qC), 130.9 (qC), 130.4 (CH), 129.1 (2 ꢁ CH), 127.9
(2 ꢁ CH), 126.4 (qC), 126.1 (CH), 125.989 (qC), 122.8 (CH), 119.6 (CH),
118.5 (CH), 116.5 (qC), 112.3 (CH), 110.6 (qC), 72.7 (qC), 43.5 (CH2),
J ¼ 16.0, 2.6, CHH). 13C NMR (100 MHz, CDCl3)
d: 195.2 (C]O), 173.3
22.0 (CH2). IR (neat, cmꢂ1
) ymax: 3359, 1679, 1660, 1606, 1558, 1456,
(qC), 163.9 (d, J ¼ 250.5 Hz, qCꢂF), 161.0 (d, J ¼ 244.0 Hz, qCꢂF),
148.7 (qC), 148.39 (qC), 130.1 (d, J ¼ 7.8 Hz, 2 ꢁ CH-mF), 127.0 (d,
J ¼ 3.1 Hz, qC-pF), 126.2 (d, J ¼ 3.5 Hz, qC-pF), 125.9 (qC), 121.8 (d,
J ¼ 4.7 Hz, qC-CCF), 116.7 (d, J ¼ 21.8 Hz, CHo-F), 114.8 (d, J ¼ 21.2 Hz,
CHo-F),114.4 (qC),111.1 (CH),108.9 (CH), 86.8 (d, J ¼ 181.3 Hz, CH2F),
70.7 (d, J ¼ 18.3 Hz, qCCH2F), 56.2 (OCH3), 55.9 (OCH3), 41.8 (CH2),
1446, 1412, 1337, 1312, 1299, 1256, 1224, 1165, 1104, 1042, 1028, 797,
781, 693, 649, 610, 519; HRMS: [M þ Naþ] for C52H38N4NaO2
calculated 773.2893, found 773.2884. X-ray crystallographic studies
[39] confirmed the structural assignment.
Azoninoindole 60: 1H NMR (400 MHz, CDCl3)
d: 10.21 (1H, s,
NH), 8.43 (1H, d, J ¼ 5.0 Hz, ArH), 8.14e8.10 (4H, m, 3 ꢁ ArH þ CH]
29.3 (CH2); IR (neat, cmꢂ1
) ymax: 2924.5, 2852.9, 1662.2, 1602.8,
CH), 7.60e7.30 (12H, m, 2 ꢁ Ph þ CH]CH þ CHPh); 13C NMR
1513.8, 1262.7, 1225.6, 1155.9, 1022.2.; HRMS: [M þ Naþ] for
(100 MHz, CDCl3) d: 198.4 (C]O), 195.1 (C]O), 141.1 (qC), 138.3
C
27H22F3NNaO3 calculated 488.1453, found 488.1438.
(CH), 136.4 (qC), 136.1 (qC), 134.3 (qC), 133.2 (qC), 133.1 (CH), 131.8
(qC), 130.3 (CH), 129.4 (CH), 129.2 (CH), 128.8 (CH), 128.7 (CH), 127.9
(CH), 121.9 (CH), 120.9 (CH), 120.6 (qC), 119.3 (CH), 112.0 (CH), 61.4
(CH); IR (neat, cmꢂ1
) ymax: 3304, 2954, 2919, 2851, 1729, 1462, 1377,
5.14. Synthesis of 8,9-Dimethoxy-5,10b-dimethyl-2,3-phenyl-5,6-
dihydropyrrolo[2,1-a]isoquinolin-1-one (57d)
1270, 1120, 1071, 1093, 741, 703; HRMS: [Mþ] for C26H18N2O2
calculated390.1368, found 390.1375.
6,7-Dimethoxy-1,3-dimethyl-3,4-dihydroisoquinoline
[39]
5.16. Synthesis of methyl 3-(1-oxo-2,3-diphenyl-6,11-dihydro-1H-
(0.0424 g, 0.1933 mmol) and diphenylcyclopropenone (0.0250 g,
0.1212 mmol) were dissolved in acetonitrile (5 mL). The solution
was stirred vigorously at 82 ꢀC for 4.5 h. After heating, excess sol-
vent was removed in vacuo. The crude material was purified via
column chromatography with standard silica eluted with 42% ethyl
acetate in hexane. The solvent was removed under pressure and
vacuum, yielding a yellow solid (0.0423 g, 78%), m.p. 189e193 ꢀC. Rf
0.33 (ethyl acetate/hexane, 42:58); 1H NMR (300 MHz, CDCl3), ~2:5
indolizino[8,7-b]indol-11b(5H)-yl)propanoate (69)
To a stirred solution of methyl 3-(4,9-dihydro-3H-pyrido[3,4-b]
indol-1-yl)propanoate 65 [44] (0.06 g; 0.24 mmol) in acetonitrile
(5 mL), was added diphenylcyclopropenone (0.05 g; 0.24 mmol) at
room temperature under an atmosphere of nitrogen. The reaction
mixture was stirred at room temperature for 24 h and the solvents
were removed by rotary evaporation under reduced pressure. The
crude product was purified by flash silica chromatography afford-
ing the title compound as an orange yellow solid (0.09 g, 81% yield),
m.p. 182e183 ꢀC. Rf 0.35 (ethyl acetate/hexane, 1:1); 1H NMR
mixture of diastereoisomers, d: 7.91e7.40 and 7.13e7.01 (11H, m,
ArH þ 2Ph, mixture of diastereoisomers), 6.64 and 6.51 (1H, 2 ꢁ s,
ArH), 4.30e4.22 (1H, m, CHMe), 4.01 and 3.99 (3H, 2 ꢁ s, OMe), 3.86
and 3.84 (3H, 2 ꢁ s, OMe), 3.20 and 2.80 (1H, 2 ꢁ dd, J ¼ 15.4, 3.9 Hz
and 15.6, 6.0 Hz, CHH), 2.62 and 2.39 (dd and d, J ¼ 15.4, 5.7 Hz and
15.6 Hz, CHH), 1.83 and 1.35 (3H, 2 ꢁ s, Me),1.37 and 0.69 (3H, 2 ꢁ d,
(400 MHz, CDCl3) d: 9.27 (1H, s, NH), 7.57e7.53 (2H, m, Ar), 7.47 (2H,
d, J ¼ 7.8 Hz, Ar), 7.43 (2H, d, J ¼ 8.3 Hz, Ar), 7.24e7.09 (8H, m, Ar),
4.08 (1H, dd, 5.4 and 13.9 Hz, CHH), 3.63 (3H, s, CH3), 3.59e3.55
(1H, m, CHH), 2.89e2.81 (1H, m, CHH), 2.75 (1H, dd, J ¼ 15.5 and
4.0 Hz, CHH), 2.71e2.56 (3H, m, CHH þ CH2), 2.53e2.45 (1H, m,
J ¼ 7.2 and 6.6 Hz, CHCH3). 13C NMR (75 MHz, CDCl3)
d: 199.8/199.2
(C]O), 173.3/172.2 (qC), 148.2/148.1 (qC), 147.9/147.8 (qC), 132.6/
131.9 (qC),131.8/131.7 (qC),130.2/129.9 (qC),129.2 (CH) 128.9/128.7
(CH), 128.5/128.4 (CH), 128.1/127.7 (CH), 126.8 (qC), 125.5/125.3
(CH), 122.3 (qC), 115.5/114.1 (qC), 111.5/111.2 (CH), 109.7/108.3 (CH),
68.7/67.4 (qC), 56.1/55.91 (OCH3), 55.86 (OCH3), 50.9/48.7 (CH),
CHH); 13C NMR (100 MHz, CDCl3)
d: 197.7 (C]O), 175.8 (C]O),
173.3 (qC), 136.8 (qC), 131.3 (qC), 131.0 (qC), 130.7 (qC), 130.5 (CH),
129.2 (CH), 128.6 (2CH), 127.9 (CH), 126.4 (CH), 125.9 (CH), 122.4
(CH), 119.7 (CH), 118.3 (CH), 115.7 (qC), 111.9 (qC), 107.1 (qC), 69.6
(qC), 51.8 (CH3), 41.7 (CH2), 31.9 (CH2), 28.8 (CH2), 22.4 (CH2); IR
36.6/35.2 (CH2), 29.5/28.7 (CH3), 20.2/20.0 (CH3); IR (neat, cmꢂ1
)
ymax: 2929, 2831,1655,1603,1516,1464, 1423,1352,1317,1261,1211,
1140, 1082, 1041, 997, 930, 854, 748, 731, 690, 538; HRMS: [M þ Hþ]
for C28H28NO3, calculated 426.2074, found 426.2068.
(neat, cmꢂ1
)
ymax: 3269, 2928, 2839, 1744, 1639, 1601, 1536, 1469,
1428, 1351, 1171, 1060, 859, 736, 694, 511; HRMS: [Mþ] for
30H26N2O3 calculated 462.1943, found 462.1939.
C

10
F. Jamshaid et al. / Tetrahedron 76 (2020) 131570
[3] D.K. Tiwari, K.C. Bharadwaj, V.G. Puranik, D.K. Tiwari, Org. Biomol. Chem. 12
(2014) 7389e7396.
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4211e4220.
5.17. Synthesis of methyl 4-(1-oxo-2,3-diphenyl-6,11-dihydro-1H-
indolizino[8,7-b]indol-11b(5H)-yl)butanoate (70)
[5] J. Robertson, K. Stevens, Nat. Prod. Rep. 34 (2017) 62e89.
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11 (2013) 3187e3202.
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C.-Y. Yu, Org. Lett. 17 (2015) 716e719.
[10] P. Fu, S. La, J.B. MacMillan, J. Nat. Prod. 79 (2016) 455e462.
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(2018) 158e161.
To a stirred solution of methyl 4-(4,9-dihydro-3H-pyrido[3,4-b]
indol-1-yl)butanoate 66 [44] (0.12 g, 0.44 mmol) in acetonitrile
(5 mL), was added diphenylcyclopropenone (0.09 g, 0.44 mmol) at
room temperature under an atmosphere of nitrogen. The reaction
mixture was stirred at room temperature for 24 h and the solvents
were removed by rotary evaporation. The crude product was pu-
rified by flash silica chromatography affording the title compound
as an orange yellow solid (0.17 g, 80% yield), m.p. 180e181 ꢀC. Rf
0.32 (ethyl acetate/hexane, 1:1); 1H NMR (400 MHz, CDCl3)
d: 8.96
(1H, bs, NH), 7.52e7.48 (4H, m, Ar), 7.42 (1H, d, J ¼ 7.8 Hz, Ar), 7.40
(1H, d, J ¼ 8.1 Hz, Ar), 7.20 (1H, t, J ¼ 7.5 Hz, Ar), 7.14e7.03 (7H, m,
Ar), 4.11 (1H, dd, J ¼ 13.9 and 5.6 Hz, CH2), 3.70 (3H, s, CH3),
3.59e3.53 (1H, m, CH2), 2.72 (1H, dd, J ¼ 15.4 and 4.1 Hz, CH2),
2.60e2.54 (1H, m, CH2), 2.53e2.30 (3H, m, CH2), 2.25e2.17 (1H, m,
[13] K.R. Bailey, A.J. Ellis, R. Reiss, T.J. Snape, N.J. Turner, Chem. Commun. (2007)
3640e3642.
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Chem. 79 (2014) 7380e7390.
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M. Sarvestani, K.R. Fandrick, J.L. Stockdill, N. Grinberg, N. Gonnella, H. Lee,
C.H. Senanayake, Org. Lett. 18 (2016) 6192e6195.
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H. Lechner, N. Richter, E. Eger, W. Kroutil, Angew. Chem. Int. Ed. 57 (2018)
10683e10687.
CH2), 1.78e1.67 (2H, 2 ꢁ m, CH2); 13C NMR (100 MHz, CDCl3)
d:
197.9 (C]O), 175.4 (C]O), 173.6 (qC), 136.7 (qC), 131.8 (qC), 131.1
(qC),130.7 (qC),130.4 (CH), 129.1 (CH) 128.4 (CH), 127.8 (2CH), 126.5
(qC), 125.7 (CH), 122.4 (CH), 119.7 (CH), 118.3 (CH), 115.0 (qC), 111.7
(CH), 106.9 (qC), 70.0 (qC), 51.6 (CH3), 41.6 (CH2), 36.7 (CH2), 33.7
[17] P. Mondal, N.P. Argade, Synthesis 46 (2014) 2591e2594.
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K. Kyeremeh, S.M. Kelly, L. Trembleau, R. Ebel, M. Jaspars, Y. Yu, H. Deng,
Angew. Chem. Int. Ed. 54 (2015) 12697e12701.
(CH2), 22.4 (CH2), 19.2 (CH2); IR (neat, cmꢂ1
) ymax: 3246, 1731, 1644,
1538, 1422, 1351, 1315, 1254, 1083, 988, 908, 769, 696, 511; HRMS:
€
[20] O. Schimming, V.L. Challinor, N.J. Tobias, H. Adihou, P. Grün, L. Poschel,
[Mþ] for C31H28N2O3 calculated 476.2089, found 476.2100.
C. Richter, H. Schwalbe, H.B. Bode, Angew. Chem. Int. Ed. 54 (2015)
12702e12705.
[21] P.A. O’Gorman, T. Chen, H.E. Cross, S. Naeem, A. Pitard, M.I. Qamar,
K. Hemming, Tetrahedron Lett. 49 (2008) 6316e6319.
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4100e4103.
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11092e11108.
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Chem. 7 (2009) 4936e4942.
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548e554.
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759e764.
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P.S. Baran, J. Am. Chem. Soc. 133 (2011) 8014e8027.
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239e244.
5.18. Synthesis of methyl 4-(2,3-bis(4-methoxyphenyl)-1-oxo-6,11-
dihydro-1H-indolizino[8,7-b]indol-11b(5H)-yl)butanoate (71)
ꢀ
ꢀ
ꢀ
ꢀ
To a stirred solution of methyl 4-(4,9-dihydro-3H-pyrido[3,4-b]
indol-1-yl)butanoate 66 [44] (0.15 g; 0.55 mmol) in acetonitrile
(5 mL), was added 2,3-bis(4-methoxyphenyl) cycloprop-2-en-1-
one (0.15 g; 0.55 mmol) at room temperature under an atmosphere
of nitrogen. The reaction mixture was stirred at room temperature
for 24 h and then solvents were removed rotary evaporation under
reduced pressure. The crude product was purified by flash silica
chromatography affording the title compound as an orange yellow
solid (0.22 g, 74%), m.p. 188e189 ꢀC. Rf 0.72 (ethyl acetate/hexane,
1:1); 1H NMR (400 MHz, CDCl3)
d
: 9.09 (NH), 7.42 (1H, d, J ¼ 7.8 Hz,
Ar), 7.38 (1H, d, J ¼ 8.2 Hz, Ar), 7.32e7.25 (3H, m, Ar), 7.18 (1H, t,
J ¼ 7.4 Hz, Ar), 7.09 (1H, t, J ¼ 7.4 Hz, Ar), 7.03e6.98 (3H, m, Ar), 6.70
(2H, d, J ¼ 8.8 Hz, Ar), 4.16 (1H, dd, J ¼ 13.9 Hz, 5.4 Hz, CH2), 3.70
(3H, s, CH3), 3.57 (3H, s, CH3), 3.55 (3H, s, CH3), 3.54e3.35 (1H, m,
CH2), 2.69 (1H, dd, J ¼ 15.4 Hz, 3.9 Hz, CH2), 2.58e2.31 (4H, m, CH2),
2.22e2.15 (1H, m, CH2), 1.82e1.79 (1H, m, CH2), 1.74e1.71 (1H, m,
CH2); 13C NMR (100 MHz, CDCl3)
d: 198.0 (C]O), 174.9 (C]O), 173.7
(qC), 161.1 (qC), 157.6 (qC), 136.7 (qC), 132.0 (qC), 130.3 (qC), 129.7
(CH), 129.1 (qC), 126.5 (qC), 123.8 (qC), 122.7 (qC), 122.2 (CH), 119.6
(CH), 118.2 (CH), 114.5 (CH), 113.4 (CH), 111.7 (CH), 106.8 (CH), 69.9
(qC), 55.4 (CH3), 55.1 (CH3), 51.6 (CH3), 41.8 (CH2), 36.6 (CH2), 33.7
[40] S.-W. Liu, C. Yuan, X.-F. Jiang, X.-X. Wang, H.-L. Cui, Asian J. Org. Chem. 9
(2020) 82e85.
(CH2), 22.3 (CH2),19.3 (CH2); IR (neat, cmꢂ1
) ymax: 3270, 2929, 2839,
[41] M.C. Nakhla, J.L. Wood, J. Am. Chem. Soc. 139 (2017) 18504e18507.
[42] Y. Mirabal-Gallardo, M.D.P.C. Soriano, J. Caballero, J. Alzate-Morales,
M.J. Simirgiotis, L.G. Santos, Synthesis 44 (2012) 144e150.
[43] CCDC deposit number 1977885, Crystallographic data has been deposited at
the Cambridge Crystallographic Data Centre. Copies of this data can be ob-
tained free of charge on application to CCDC, Union Road, Cambridge, CB2
1EZ, UK at, www.ccdc.cam.ac.uk/data_request/cif, 12.
1742,1635, 1606,1577, 1519,1462,1437,1344,1295, 1243,1171,1023,
829, 759, 580; HRMS: [Mþ] for C33H32N2O5 calculated 536.2311,
found 536.2308.
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