Deconjugative alkylation/Heck reaction as a simple platform for dihydronaphthalene synthesis

Article abstract of DOI:10.1039/C6OB02250B

A simple platform for carbocycle synthesis by Knoevenagel adduct deconjugative alkylation/Heck reaction is described. Deconjugative alkylation of Knoevenagels adducts is two-fold synthetically enabling because C-C bond formation is (1) operationally simple due to the ease of Knoevenagel adduct carbanion generation and (2) results in alkene migration, which poises the substrate for cyclization. Furthermore, the gem-dinitrile moiety serves as a functional group for synthetic manipulation.

Full text of DOI:10.1039/C6OB02250B

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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DOI: 10.1039/C6OB02250B
Chemical Science
ARTICLE
Received 00th January
20xx,
Deconjugative alkylation/Heck reaction as a simple platform for
dihydronaphthalene synthesis
Primali Navaratne and Alexander J. Grenning*
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A simple platform for carbocycle synthesis by Knoevenagel adduct deconjugative alkylation/Heck reaction is described.
Deconjugative alkylation of Knoevenagels adducts is two-fold synthetically enabling because (1) C–C bond formation is
operationally simple due to the ease of Knoevenagel adduct carbanion generation and (2) results in alkene migration,
which poises the substrate for cyclization. Furthermore, the gem-dinitrile moiety serves as a functional group for synthetic
manipulation.
In continued studies, we reasoned that aryl acetone-derived
Knoevenagel adducts 1 and o-bromo-benzylic electrophiles 2
could react as described in Scheme 1 to yield useful cyclic
Introduction
Knoevenagel adducts have attractive chemical attributes.
They are prepared from abundant ketones and malonic acid
derivatives by an eco-friendly condensation reaction.1 Of
specific interest to this work, they have highly acidic γ-C–H
bonds, which allow for operationally simple activation to their
respective allyl carbanions for coupling reactions.2–4 Upon
deconjugative alkylation (γ-deprotonation/α-alkylation),2 the
alkylidene-olefin cannot re-conjugate unlike mono-electron-
withdrawing group analogues (i.e. when E2 = H) (Scheme 1). A
synthetic platform that takes advantage of the dual nature of
deconjugative alkylation (C–C bond formation and olefin
migration) for carbocyclization via a broadly defined “pairing”
reaction has the potential to be a straightforward approach to
the synthesis of useful chemical architectures. On this line, the
malonic acid moiety, which is critical for implementing the
chemistry, is situated within the carbocycle and would serve as
a useful functional group for further manipulation to target
structures.
scaffolds. As described in Scheme 2, Knoevenagel adduct 1
could undergo directed deconjugative alkylation (by
deprotonation of the most acidic γ-C–H as shown to Ia)2 with
o-bromo-benzylic electrophiles 2 yielding 3. The deconjugative
alkylation process directly pairs the substrate for
intramolecular Heck cyclization, ideally favouring a less
common 6-endo-trig5–7 reaction pathway (over 5-exo-trig) to
yield aryl dihydronaphthalene 4 (Scheme 2). Notably, related
aryltetralins and naphthalenes have significant biological
activities and medicinal relevance.8–12 If achieved, the
proposed tetralin scaffolds 4 will bear a gem-dinitrile moiety,
which will allow for access to unexplored nitrile-containing aryl
tetralin analogues 5 and 6 by utilization of reductive13,14 or
dehydrocyanation protocols.15,16 From a medicinal chemistry
perspective, nitrile inclusion would be beneficial for the
following reasons: (a) a nitrile is sterically small (A value =
0.17), (b) has noted metabolic stability, (c) changes the
lipophilicity of the molecule, and (d) is isosteric to a halogen.17
Scheme 1. General strategy for carbocycle synthesis
We4 recently disclosed that Knoevenagel adducts can
behave as trimethylenemethane dipole surrogates for reaction
with electrophiles and nucleophiles in a 3-component fashion.
Scheme 2. General hypothesis for carbocycle synthesis
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Related bicyclic scaffolds are commonly prepared by begin, we examined the deconjugative alkylation2 reaction and
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DOI: 10.1039/C6OB02250B
a benzylic found the reaction was high yielding under standard alkylation
intramolecular Friedel-Crafts alkylation with
electrophile, or by a Diels-Alder cycloaddition of o-xylylenes conditions (NaH, DMF). Notably, the Knoevenagel adduct’s
generated from various precursors.18-20 The former route is aromatic group directs the deprotonation allowing for the
considered biomimetic.19 Alternatively, 1-arylation of desired styrene-moiety to be synthesized upon α-benzylation.
preformed bicycles (tetralins, naphthalenes, or related) is also
We next examined the key intramolecular Heck cyclization
common by organometallic addition, C–H arylation, or other and found that “Jeffery” conditions23,24 worked best with an
methods.21 There are other unique cyclization strategies,22 optimized yield of 71% for dihydronaphthalene 4a (Scheme
however, of interest to the work herein, is aryl tetralin 3B). We were pleased with this result as relatively inexpensive
synthesis by intramolecular Heck cyclization,5d,7 which is poorly PdCl2 (5 mol%) could be used as a catalyst in the presence of
examined.
TBAI as an additive. That said, a variety of other conditions
were attempted and are summarized in the supporting
information. In brief, it appears that in our hands various Pd-
phosphine catalyst-combinations were poorly reactive and
only when ligandless conditions (“Jeffery conditions”) were
employed did we begin to observe the desired product 4a.
Interestingly, various bases were screened during the
optimization and we observed byproduct cyanonaphthalene
6a in some cases. The byproduct is derived from the product
4a by a base-promoted dehydrocyanation.15,16 For example,
when the more basic carbonate bases (H2O pKa ~10) were used
in lieu of KOAc (H2O pKa ~4), a significant amount of 6a was
observed (22% isolated yield). As the final point, we were also
able to perform the γ-deprotonation/α-benzylation/Heck
cyclization sequence in one-pot (56% yield from 1a and 2a).
However, we ultimately decided to examine the scope over
two steps as this yield was higher and isolation of benzylated
intermediate 3 is simple.
Figure 1. Natural products and synthetic molecules of interest
to this study
Scheme 3. Development of the formal [3+3] annulation
strategy
The proposed strategy is a unique platform for tetralin
synthesis, utilizes abundant reagent classes as sole carbon
sources (ketone + malononitrile = Knoevenagel adduct;
benzylic electrophiles), has the potential to be operationally
simple due to the ease of Knoevenagel adduct anion
generation, and would result in structurally unique 3-cyano
aryl dihydronaphthalenes 5 and aryl naphthalenes 6. For these
reasons we wished to examine the possibility of this
hypothesis.
Development and Scope of the Strategy
We chose to examine Knoevenagel adduct 1a, prepared
from p-methoxyphenylacetone and malononitrile by the Cope-
Knoevenagel procedure,1c and o-bromobenzyl iodide 2a,
prepared from commercial 6-bromoveratraldehyde, as our
initial reagents for formal [3+3]-cyclization (Scheme 3). To
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We were pleased to find that a variety of substituted aryl to prepare other uniquely substituted tetralin cores (Scheme
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tetralins 4a – 4h could be prepared by the formal [3+3]- 5). In this regard we found that a varieDtyOIo: 1f0γ.1,0γ3-d9/iCsu6bOsBt0it2u25te0dB
cyclization strategy (Scheme 4). Generally speaking the Knoevenagel adducts could afford the desired tetralin
deconjugative benzylation reactions were excellent and the products 4k – 4q in modest to good yields. For example,
Heck reaction worked best when both aromatic rings were products 4k – 4l are derived from isopropyl methyl ketone, 4m
electron rich. For example, the yield was decreased for 4d due – 4p are derived pyruvaldehyde dimethyl acetal, and 4q is
to significant formation of its naphthalene byproduct (via derived from acetoin.
dehydrocyanation). To reiterate, the electronics of the tetralin
play a key role in favouring either product 4 or byproduct 6
under the reaction conditions. The reaction was not limited to
arylacetone-derived Knoevenagel adducts as we were able to
utilize a 1,3-diphenyl-ketone Knoevenagel adduct to prepare
the tetralin 4f. We also wished to explore the scalability. As is
common with Jeffrey conditions, we were able to reduce the
catalyst loading on the 5 gram scale when preparing tetralin
4h.24 Excitingly, the reaction works excellently on the large
scale and ample material was prepared for further substrate
processing.
We also examined the cyclohexanone-derived substrate 3i
Scheme 5. Sterically-biased formal [3+3]-cyclizations
(eq. 1). Unfortunately, only decomposition was observed using
the standard protocol. The acetophenone-derived molecule 3j
was a competent coupling partner, albeit in modest yield
under the conditions optimized for arylacetone-derived
substrates (eq. 2). Interestingly, the tetralin was not observed
and we were only able to isolate the 2-phenylnaphthalene
product 4j. If further examined this could be a powerful
strategy to prepare highly substituted naphthalenes from
acetophenones, malononitrile, and benzylic electrophiles.
Scheme 4. Scope of 1-aryl tetralin synthesis
Having established that a variety of tetralin cores bearing a
gem-dicyano group can be prepared, we next examined two
different strategies to mono-decyanate the scaffolds;
reductive
decyanation13,14
and
base-promoted
and 7,
dehydrocyanation (E2 reaction) (Schemes
6
respectively).15,16 We were able to realize a reductive
decyanation reaction yielding 3-cyano aryl tetralins when using
either lithium naphthalenide14c (LN) or samarium(II) iodide14e
(SmI2) (Scheme 6). Using LN, mono-decyanation was observed
on a variety of scaffolds (4b, 4c, 4e) preparing cyanotetralins
6a – 6c. One outlier substrate was 4h, where decyanation
conditions using LN produced only double decyanation
product 6d in modest yield. At this point, other reductive
16e
conditions were examined and we found that SmI2 was an
excellent reagent for mono-decyanation of these substrates
producing 6e in 74% isolated yield.
The molecules prepared in Scheme 5 are unnatural nitrile-
containing analogues of attenuol (Scheme 5),23 magnoshinin
(Figure 1),24 and other related 2,3-dimethyl aryl tetralins.25
Such natural products have a variety of biological activities.23-25
Considering the results from our initial scope studies
(Scheme 4) and the results in equations 1 and 2, we wondered
if the γ-deprotonation/α-alkylation could be directed by sterics
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Replacement of a methyl group with a nitrile is unprecedented
both naturally and synthetically but could have interesting under Pinner reaction29 conditions to yiDeOldI:c1y0a.1n03o9a/cCe6tOicB0e2s2t5e0rBs
effects on structure-activity relationships.15
7a and 7b following hydrolysis (Scheme 8). Notably, synthesis
The gem-dinitrile moiety could also react with alcohols
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The second decyanation reaction examined was base- of the allyl cyanoacetate 7b allowed us to utilize
promoted dehydrocyanation leading to 3-cyano aryl decarboxylative allylation (DcA) to install an allyl group onto
naphthalenes 5a – 5d (Scheme 7).27,28 Cyanide is not a scaffold 7c.30 We also examined oxidative protocols for the
common leaving group, but due to the aromaticity driving naphthalene scaffolds and found that radical benzylic
force, the reaction was found to be facile under simple bromination to 7d was high yielding. The halogen could then
conditions (1.1 equiv. KOtBu, THF, 0 °C). As above, the serve as a functional handle for the incorporation of
synthetic strategy results in medicinally relevant cyano- nucleophiles (e.g. acetate, 7e) or allow further oxidation to an
containing analogues of 1-aryl naphthalene natural products. aldehyde (the Sommelet protocol was utilized, 7f).31
The parent 1-aryl-napthalene core is found in many bioactive
Scheme 8. Other scaffold manipulations
natural products.27,28
Scheme 6. Reductive decyanation produces nitrile-containing
analogues of aryl tetralin natural products
Scheme 7. Retro-hydrocyanation produces nitrile-containing
analogues of aryl naphthalene natural products
Conclusions
We have devised a platform for carbocycle synthesis that
utilizes Knoevenagel adducts as conjunctive reagents.
Knoevenagel adducts can react with bis-electrophilic o-
bromobenzyl iodides allowing for formal [3+3]-cyclization by
deconjugative benzylation then 6-endo-trig Heck cyclization.
The developed cyclization uses abundant carbon-sources, is
operationally simple, and yields useful carbocyclic frameworks.
We describe the synthesis of previously unknown 3-cyano aryl
tetralin and naphthalenes, which are being analysed for
biological activity. Future synthetic efforts are aimed at
designing related cyclization reactions for Knoevenagel
adducts based on the general reaction protocol outlined in
Scheme 1.
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