Nitromethane as a Carbanion Source for Domino Benzoannulation with Ynones: One-Pot Synthesis of Polyfunctional Naphthalenes and a Total Synthesis of Macarpine

Article abstract of DOI:10.1002/anie.201810652

A one-pot, transition-metal-free, domino Michael/S_NAr protocol of general applicability has been devised for the regioselective synthesis of polyfunctional naphthalenes by employing nitromethane and ortho-haloaryl ynones. Utilization of nitromethane as a one carbon carbanion source that is incorporated into a variety of ynones, ends up as an aromatic nitro substituent. The application of this domino process towards a total synthesis of the polycyclic alkaloid macarpine demonstrate for the efficacy of this methodology. The conceptually simple approach to affect regioselective, multifunctional benzoannulation of ynones displays wide substrate scope and functional-group tolerance and has been implemented with substituted nitromethanes, as well as with alicyclic o-haloynones.

Full text of DOI:10.1002/anie.201810652

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Nitromethane as a Recursive Carbanion Source for Domino
Benzoannulation with Ynones: One-pot Synthesis of
Polyfunctional Naphthalenes and a Total Synthesis of Macarpine
Authors: Pabbaraja Srihari, Shweta Singh, Ramesh Samineni, and
Goverdhan Mehta
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201810652
Angew. Chem. 10.1002/ange.201810652
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Nitromethane as a Recursive Carbanion Source for Domino
Benzoannulation
with Ynones: One-pot Synthesis of
Polyfunctional Naphthalenes and a Total Synthesis of Macarpine
Shweta Singh[a],† Ramesh Samineni[a], [b],† Srihari Pabbaraja*[a], Goverdhan Mehta*[c]
Abstract: A one-pot, transition-metal-free, domino Michael-SNAr
protocol of general applicability has been devised for the
regioselective synthesis of polyfunctional naphthalenes employing
nitromethane and ortho-haloaryl ynones. Utilization of nitromethane
as one carbon recursive carbanion source that is subsumed into a
variety of ynones to end up as aromatic nitro substituent has been
demonstrated. Besides many interesting examples, the application
of this domino process towards a total synthesis of polycyclic
alkaloid macarpine vouch for the efficacy of this methodology. The
conceptually simple approach to affect regioselective, multifunctional
benzoannulation of ynones displays wide substrate scope and
functional group tolerance and has been implemented with
substituted nitromethanes, reacting through a ‘split and subsume’
process, as well as with alicyclic o-haloynones.
Herein, we disclose a de novo effort via domino[12]/tandem
[13]
Michael-SNAr strategy
that fills the gap and provides a
versatile entry to polyfunctional naphthalenes with the
embedment of the desirable functional elements. We further
demonstrate efficacy of classical tactics to amplify functionality
on the naphthalene framework and as an application disclose a
total synthesis of phenanthridine alkaloid macarpine.[1e] We have
also extended the domino/tandem Michael-SNAr strategy to
access diverse benzoannulated carbocycles.
Highly functionalized naphthalenes are common, widely
distributed structural motifs which are encountered in many
important and diverse bioactive natural products and
pharmaceuticals,
(Figure
1).[1]
Recently,
substituted
naphthalenes have also drawn traction as building blocks for
electronic materials, particularly as organic field-effect
transistors for a variety of applications that range from large area
flexible displays, smart cards and sensors.[2] Consequently, short,
versatile syntheses of substituted naphthalenes have been
engaging widespread attention during the past several decades
with many notable developments.[3] These include various
functionalizations and cross coupling maneuvers on preexisting
naphthalene platform,[4]Diels Alder cycloaddition[5] or Wulff-Dötz
benzannulation[6] on appropriately pre-assembled substrates,
transition-metal/Lewis acid catalyzed cyclizations,[7] annulations
employing arynes or ring-closing metathesis[8], rearrangements
of strained rings[9] and photo-catalyzed[10] reactions among
others.[11] From this vast repertoire, a selection of newer
approaches, reported during the preceding decade, are captured
in Scheme 1.
Figure 1: Representative bioactive naphthalene containing natural products
Although many of the existing methods for the synthesis of
polyfunctional naphthalenes have their own merits and
importance, there is a void in terms of methods of general
applicability and broad substrate scope that can be executed
using operationally simple procedure (metal free, one-pot
reaction), bench-top building blocks and reagents and can
generate diverse functionalities in a regioselective manner.
Scheme 1: Representative recent synthesis of polysubstituted naphthalenes
Conceptual foundation of our new naphthalene synthesis was
based on sequential, one pot union, of two entities involving
ortho-haloarylynone moiety 7 as a dual acceptor for tandem
Michael addition and SNAr substitution and nitromethane
partner[14] 8 as one carbon recursive carbanion source, see,
Scheme 2. In this process, two new C-C bonds are formed along
with concomitant aromatization and nitromethane, as a dual
donor, is completely subsumed to show up as aromatic nitro
group in the target structure 9. Such incorporation of
nitromethane as a source of aromatic nitration, visualized here,
is quite new and has the potential for wider applications.
[a]
Dr. Shweta Singh, Dr. Ramesh Samineni, Dr. Srihari Pabbaraja*
Department of Organic Synthesis and Process Chemistry
CSIR-Indian Institute of Chemical Technology
Tarnaka, Hyderabad-500007, India
E-mail: srihari@iict.res.in
IICT manuscript communication no.IICT/PUBS./2018/284
Present Address: Dr. Ramesh Samineni, Department of Chemistry,
SRMIST, Kattankulathur, Chennai-603203, India
Prof. Goverdhan Mehta,*School of Chemistry, University of
Hyderabad, Hyderabad- 500046, India.
[b]
[c]
E-mail: gmehta43@gmail.com
Supporting information for this article is given via a link at the end of
the document.
Scheme 2: Our conceptualization for polysubstituted naphthalenes
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To implement the conceptual framework depicted in Scheme 2,
studies, it was observed, not quite unexpectedly, that the
nitromethane insertion to furnish highly substituted naphthalenes
9t and 9u, respectively, was less efficient with electron rich
ynones 7v and 7w (Scheme 5).
reaction between
a
model o-bromoaryl ynone [1-(2-
bromophenyl)-3-phenylprop-2-yn-1-one] 7a and nitromethane 8
was performed. Several bases like Na2CO3, K2CO3, Cs2CO3 and
DBU were explored but under optimized conditions {Cs2CO3 (2.0
equiv), DMF, 100 oC, 12 h, see Supporting Information (SI)}, the
reaction afforded, as projected, 4-nitro-a-naphthol product 9a in
92% yield (Scheme 3). It was also established that 4-nitro-a-
naphthol (9a) formation proceeded with equal felicity employing
other o-halogen substituted aryl ynones 7b (X = Cl) and 7c (X =
F) to deliver naphthalene derivative 9a. To glean validating
evidence about the involvement of the proposed tandem Michael
addition - SNAr steps in the formation of 9a, the reaction of 7a
leading to 9a was performed at ambient temperature using same
reagents and solvent. This protocol delivered the intermediate
Michael addition product 10 in 85% yield and its further
exposure to Cs2CO3 (1.0 equiv) at higher temperature, under
optimized conditions, led to naphthalene derivative 9a. Indeed,
this 4-nitro-3-phenyl-1 naphthol 9a can be readily prepared on
gram scale, enabling further useful explorations, particularly
amplification and tuning of functionality employing classical
manipulations around it, as displayed in Scheme 4. This
includes reductive insertion of the nitro group in the methyl ether
13 into the pendant aryl ring via Cadogan cyclisation[15] to furnish
benzocarbazole 14.
Scheme 5: Reaction of nitromethane with various substituted o-haloaryl
ynones
Scheme 3: Synthesis of polysubstituted naphthols
Scheme 6: Possible reaction mechanism
A plausible reaction mechanism for the new domino process is
indicated in Scheme 6. An initial Michael addition of
nitromethane anion onto ynone 7a leads to intermediate A which
tautomerises to enone
B
(isolated and characterized).
Scheme 4: Selected transformations of 9a
Reiterative carbanion generated from B displaces the aromatic
bromide in a SNAr reaction to deliver intermediate C, which
aromatizes to substituted naphthalene 9a.
At this stage, it was important to demonstrate the generality and
substrate scope of this domino Michael-SNAr reaction. Towards
this end, we have explored the substrate scope employing o-
bromoaryl ynones (7d-p) having diverse substitutions (aryl,
pyridyl, naphthyl, alkyl, hydrogen) attached to triple bond leading
to the formation of functionalized naphthalenes (9b-n)
respectively (Scheme 5). To amplify functional group density
and diversity of substitution pattern on the naphthalenes,
variously substituted o-haloaryl ynones (7q-w) were engaged
with nitromethane under the standard conditions to furnish the
corresponding polyfunctional naphthalenes 9o-u. During these
To further leverage the advantageous outcome with the
recursive carbanion from nitromethane for naphthalene
synthesis, it was of interest to deploy its activated derivatives
like ethyl nitroacetate 8a and benzoyl nitromethane 8b as
reaction partners with o-bromoaryl ynones 7a, p, w. Under the
optimized conditions, the reaction occurred smoothly, but took
an unexpected deviant course to deliver highly substituted
naphthalenes 16a-f instead of the expected products like 17.
This stratagem has paved a way for one-pot benzoannulation
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with four different functional groups (hydroxy, ester/benzoate,
aryl/alkyl and nitro) on four consecutive sp2-carbons to deliver
poly-substituted naphthalenes, (scheme 7).
moiety as a total synthesis objective. This tetracyclic alkaloid
was isolated from Macleaya cordata and other papaveraceous
plants and displayed cytotoxic activity against HeLa S3 tumor
cell lines with an IC50 of 0.192 mg/mL.[1e] Our synthetic approach
to macarpine 3 was delineated through a retrosynthetic analysis
in which 4-nitronaphthalene derivative 19 was to serve as a
pivotal intermediate, Scheme 9. Accordingly, macarpine 3 could
be synthesized from the known N-methylated aldehyde 18 via
cyclization and dehydration reaction sequence. Aldehyde 18
inturn could be generated from the pivotal naphthalene
derivative 19 via nitro group reduction and to amine and N-
substitution reactions. The key functionalized naphthalene 19
was to be accessed via the domino Michael-SNAr reaction of
nitromethane with suitably crafted ynone precursor 20, which
could be assembled from aldehyde 21 and alkyne 22.
Scheme 7: Synthesis of highly substituted naphthalenes
Scheme 8: Possible reaction mechanism
A possible mechanism for the formation of 16a-f involves
Michael addition of anion derived from activated nitromethane
(8a, b) to ynone 7 to afford intermediate D, which readily
collapses to strained cyclobutene[13d-f] intermediate E before C-C
bond cleavage to deliver enone F. The recursive carbanion from
Intermediate F undergoes SNAr reaction to bicyclic intermediate
G enroute aromatization to tetrasubstituted naphthalene 16a-f,
Scheme 8. Overall, in this deviant albeit interesting reaction
course, directed by a bystander carbonyl group (D→E) the two
functionalities of activated ethyl nitroacetate 8a and benzoyl
nitromethane 8b are ‘split’, subsumed and show up as 1,3-
substitition on the naphthalene framework.
Scheme 10: Total synthesis of macarpine 3
The synthesis was initiated by synthesizing the suitable ynone
20 through the addition of alkyne 22 to o-bromo-aldehyde 21
further oxidation to ynone 20. The key Michael-SNAr
benzoannulation reaction between ynone 20 and nitromethane
was performed under optimized conditions to furnish 4-nitro-a-
naphthol 19 in good yield and was further O-methylated to 23.
The nitro functionality in 23 was directly transformed to N-CHO
in one-pot protocol[16] using Pd/C and NH4COOH and was further
N-methylated to provide the known compound 18. By following
the precedented steps,[1e] 18 was elaborated to the natural
product macarpine 3 and its spectral data was in complete
agreement with those reported in the literature, (Scheme10).
Is our benzoannulation protocol an exclusive preserve of o-
haloaryl ynone substrates or has wider implications? To probe
Scheme9: Retrosynthetic analysis of macarpine3
this question, we have investigated b-bromoalkenylynone[13c]
-
nitromethane domino reaction, an alicyclic equivalent of our o-
bromoaryl ynone based naphthalene synthesis. Four different
carbocyclic ynones (24a-d) were readily assembled and their
banzoannulation with nitromethane under optimized conditions
proceeded flawlessly and efficiently to deliver functionalized
indane 25a, tetralin 25b, benzosuberane 25c and 9,10-
The ease and efficacy of this new naphthalene synthesis
opened the avenues for diverse natural product synthesis
embodying this motif. As a demonstrator in this quest, we
targeted bioactive, polyoxygenated benzo[c]phenanthridine
alkaloid natural product macarpine 3, embodying a naphthalene
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regioselectively furnish highly substituted nitronaphthalenes. This
one pot methodology has been applied to achieve a total synthesis
of benzo[c]phenanthridine alkaloid macarpine and further extended
to substituted nitromethanes which react through a ‘split and
subsume’ process to amplify functional diversity pattern and to
alicyclic o-haloynones to deliver various benzocarbocylic scaffolds.
We believe that the methodology unveiled here will be a convenient
and efficacious enabler for accessing a range of polycyclic aromatics
for bio- and materials applications.
Acknowledgements
This research was under the Indo-French “Joint Laboratory for
Natural Products and Synthesis towards Affordable Health
(NPSAH)", and supported jointly by the Council of Scientific and
Industrial Research (CSIR) and Department of Science and
Technology (DST), New Delhi under project code GAP-584. GM
thanks Dr. Reddy’s Laboratory (DRL) for the award of Dr. Kallam
Anji Reddy Chair Professorship. We thank Dr. Amala and Mr.
Showkat Rashid of UOH for their help in X-ray structure
determination.
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Keywords: nitromethane• domino reaction•SNAr reaction•
substituted naphthalenes• macarpine• benzocarbazoles•
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
A
one-pot,
transition-metal-free,
Shweta Singh, Ramesh Samineni,
domino Michael-SNAr protocol of
general applicability has been devised
for the regioselective synthesis of
Srihari Pabbaraja, Goverdhan Mehta
Page No. 1– Page No.4
polyfunctional
employing nitromethane and ortho-
haloaryl ynones. Utilization of
nitromethane as one carbon recursive
carbanion source that is subsumed
into a variety of ynones to end up as
aromatic nitro substituent has been
naphthalenes
Nitromethane
Carbanion
Benzoannulation with Ynones: One-
pot Synthesis of Polyfunctional
Naphthalenes and a Total Synthesis
of Macarpine
as
Source
a
Recursive
for Domino
demonstrated.
Besides
many
interesting examples, the application
of this domino process towards a total
synthesis of polycyclic alkaloid
macarpine vouch for the efficacy of
this methodology. The conceptually
simple
approach
to
affect
regioselective,
multifunctional
benzoannulation of ynones displays
wide substrate scope and functional
group tolerance and has been
implemented
with
substituted
nitromethanes, reacting through
a
‘split and subsume’ process, as well
as with alicyclic o-haloynones.
This article is protected by copyright. All rights reserved.