Synthesis of Fused Indoline-Cyclobutanone Derivatives via an Intramolecular [2+2] Cycloaddition

Article abstract of DOI:10.1002/ejoc.201900326

A serendipitously-discovered process for the synthesis of heterocyclic products containing a novel fused indoline-cyclobutanone ring system is reported. This process is believed to take place through in situ generation of a ketene intermediate, followed b

Full text of DOI:10.1002/ejoc.201900326

A Journal of
Accepted Article
Title: Synthesis of Fused Indoline-Cyclobutanone Derivatives via an
Intramolecular [2+2] Cycloaddition
Authors: Rifahath Neyyappadath, Mark Greenhalgh, David Cordes,
Alexandra Slawin, and Andrew David Smith
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900326
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10.1002/ejoc.201900326
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Synthesis of Fused Indoline-Cyclobutanone Derivatives via an
Intramolecular [2+2] Cycloaddition
Rifahath M. Neyyappadath,[a] Mark D. Greenhalgh,[a] David B. Cordes,[a] Alexandra M. Z. Slawin,[a] and
Andrew D. Smith*[a]
Abstract: A serendipitously-discovered process for the synthesis of
heterocyclic products containing novel fused indoline-
protocol has been extended for the synthesis of various
carbocycles and oxygen-containing heterocycles[7] and applied
in numerous natural product syntheses;[8] however to date there
have only been two applications of intramolecular aldol-
lactonization for the synthesis of enantioenriched nitrogen-
containing heterocycles.[9]
a
cyclobutanone ring system is reported. This process is believed to
take place through in situ generation of a ketene intermediate,
followed by intramolecular [2+2] cycloaddition with a pendant
enamide. The formation of a ketene intermediate in this process is
significant as the reaction conditions employed are analogous to
those commonly used in tertiary amine Lewis base catalysis, where
the potential intermediacy of ketenes is an important consideration
that is often overlooked.
Introduction
Nitrogen-containing heterocycles constitute a privileged class of
organic compounds, due to their prevalence within natural
products and bioactive compounds.[1] The importance of
nitrogen-containing heterocycles in pharmaceuticals is
highlighted by the fact that 59% of all FDA-approved small-
molecule drugs contain at least one nitrogen heterocycle.[1b] On
average, 28% of all new small-molecule drugs approved each
year also feature a new ring system,[1c] compounding the
importance of developing methodologies that provide access to
novel heterocyclic ring systems. Of particular interest are ring
systems that contain sp3-hybidized carbons that can open up
new vectors to explore 3D chemical space.[1b–d,2]
C(1)-Ammonium enolate catalysis has been widely utilized for
the diastereo- and enantioselective synthesis of carbo- and
heterocyclic compounds.[3] In 2001, Romo introduced an
intramolecular aldol-lactonization protocol, using a cinchona
alkaloid-derived catalyst 3, for the synthesis of enantioenriched
bicyclic β-lactones 4 (Scheme 1a).[4] This transformation was
proposed to proceed via the key C(1)-ammonium enolate
intermediate 8 (Scheme 1b), which was formed following
functionalization of the carboxylic acid of substrate 1 using
Mukaiyama’s reagent 2.[5] Although the generation of ketenes
from carboxylic acids following functionalization with
Scheme 1. Cinchona alkaloid-catalyzed aldol-lactonization
Our group subsequently extended the utility of C(1)-ammonium
enolate catalysis through the development of isothiourea-
catalyzed intramolecular Michael addition-lactonization protocols
for the enantio- and diastereoselective synthesis of carbocyclic
and heterocyclic products 12 (Scheme 2a).[10] In these
methodologies, optimal yields were obtained when pivaloyl
chloride 10 was used for the in situ conversion of the carboxylic
acid to a mixed anhydride. Application of this method for the
synthesis of nitrogen-containing heterocycles has again
remained notably under-developed, with only two examples
disclosed to date.[11] In the method reported for the synthesis of
pyrrolidines 14,[11a] isolation of the requisite enone-acid
Mukaiyama’s reagent
2
has been reported,[6] the high
enantioselectivity obtained in this protocol suggested that either
formation of (C1)-ammonium enolate 8 was achieved without the
intermediacy of a ketene 7 (Scheme 1b, Path A), or that the
ketene intermediate 7 was trapped by the tertiary amine catalyst
3 significantly faster than the rate of [2+2] cycloaddition with the
pendant aldehyde to give racemic β-lactone (±)-4 (Scheme 1b,
Path B). The scope of this intramolecular aldol-lactonization
substrates proved inefficient and therefore
a telescoped
procedure was adopted, which involved sequential ozonolysis,
Wittig olefination and isothiourea-catalyzed Michael addition-
lactonization (Scheme 2b).
[a]
Dr R. M. Neyyappadath, Dr M. D. Greenhalgh, Dr D. B. Cordes,
Prof. A. M. Z. Slawin, Prof. A. D. Smith
EaStCHEM, School of Chemistry, University of St Andrews, St
Andrews, Fife, KY16 9ST, UK.
E-mail: ads10@st-andrews.ac.uk
http://chemistry.st-andrews.ac.uk/staff/ads/group
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201900326
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COMMUNICATION
temperatures and shorter reaction times, in addition to an
analogous Horner-Wadsworth-Emmons approach, also did not
provide selective formation of the desired enone. An alkene
cross-metathesis between N-allyl-N-tosylamine 20 and methyl
vinyl ketone using Grubbs 2nd generation catalyst was also
attempted, but no enone was observed and only starting
material recovered.
Scheme 4. Substrate synthesis
Scheme 2. Isothiourea-catalyzed Michael addition-lactonization
Despite the difficulties identified in accessing the desired enone
substrate, it was reasoned that the basic conditions used in
To address these current deficiencies within (C1)-ammonium
enolate catalysis, we sought to apply a Michael addition-
lactonization strategy for the synthesis of novel nitrogen-
containing heterocycles. Based on our recent work detailing the
synthesis of cis-chromenone derivatives,[10c] it was believed that
6-exo-trig cyclization of enone-acids 15 could provide access to
stereo-defined tetrahydroisoquinoline derivatives 16 (Scheme
3).[12] Reported herein are studies towards these heterocycles,
which resulted in the serendipitous discovery of a synthetic
protocol to access novel indoline-cyclobutanone products 18,
formed through an intramolecular [2+2] cycloaddition involving
an in situ-generated ketene (Scheme 3).
isothiourea-catalyzed Michael
addition-lactonization may
promote tautomerization of enamide 21 to the desired enone in
situ. Accordingly, enamide 21 was treated with pivaloyl chloride
10 and i-Pr2NEt in CHCl3 at room temperature for 15 minutes,
followed by the addition of tetramisole·HCl 11 and additional i-
Pr2NEt
(Scheme
5).
Formation
of
the
expected
tetrahydroquinoline was not observed, with the only isolable
product identified as fused indoline-cyclobutanone derivative 22
by single crystal X-ray crystallographic analysis.[15] Indoline
derivative 22 was isolated in 42% yield as
a single
diastereoisomer, but HPLC analysis using a chiral support
confirmed it was obtained as a racemate (entry 1). In an attempt
to promote enantioselectivity, 20 mol% of tetramisole·HCl 11
was added at the outset of the reaction, however indoline
derivative 22 was still obtained as a racemate (entry 2). These
resulted indicated that enantioinduction may be challenging, and
therefore the use of simple achiral Lewis bases was investigated.
Using either 4-dimethylaminopyridine (DMAP) or 1,4-
diazabicyclo[2.2.2]octane (DABCO) provided comparable yields
of (±)-22 (42–43%, entries 3 and 4). Finally, the use of only
pivaloyl chloride and i-Pr2NEt, in the absence of an additional
Lewis base catalyst, gave (±)-22 in 46% yield (entry 5).
Scheme 3. Attempted isothiourea-catalyzed enantioselective synthesis of
tetrahydroquinoline derivatives 16, and resulting discovery of process to
access indoline-cyclobutanone derivatives 18
Results and Discussion
Synthesis of Model Substrate and Reaction Optimization
Initial studies focused on the development of a synthetic route to
the requisite enone-acid substrates 15. N-Allyl-N-tosylamine 19
could be accessed in three steps from commercially-available
aminoalcohol 20 in 72% overall yield.[13] Subjecting 20 to an
ozonolysis/Wittig olefination sequence did not lead to the
expected enone, with enamide 21 instead isolated as a 88:12
ratio of (E)- and (Z)-isomers.[14] The use of lower reaction
Scheme 5. Unexpected formation of indoline-cyclobutanone fused product 22,
and representation of structure based on single crystal X-ray crystallographic
a
analysis. Majority of hydrogen atoms omitted for clarity. 11 added at start of
reaction. b not applicable. c i-Pr2NEt (2 equiv.), t-BuCOCl 10 (2 equiv.), r.t., 2 h.
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COMMUNICATION
Although unexpected, both the mechanism of formation and the
3D structure of this heterocyclic product were intriguing. A
survey of the literature revealed that although fused indoline ring
systems are common within natural products and bioactive
compounds,[16] very few examples of indoline derivatives fused
to 4-membered rings have been reported.[17] Considering the
importance of developing methods that provide access to novel
heterocyclic ring systems,[1b,c] further studies into the formation
of these fused indoline-cyclobutanone derivatives were pursued.
Table 1. Substrate Scope.
Reaction Scope and Limitations
The scope and limitations of this method for accessing novel
fused indoline ring systems was investigated. The enamide
substrates were prone to hydrolysis upon purification or storage,
and were therefore used immediately after preparation (see
Scheme 4 for synthetic approach).[13] The scope of the synthetic
process was first studied using enamide-acid substrates bearing
different pendant ketones (Table 1). The introduction of either
electron-withdrawing or -donating groups on the aryl ketone was
tolerated, with products 23–26 obtained in moderate to good
yield (38–64%).[18] The method was equally effective for alkyl-
substituted ketones, with 27 obtained in 53% yield, however
changing the ketone to an ester resulted in a complex mixture of
products. Changing the N-substituent to N-mesyl was also well
tolerated, giving product 28 in 57% yield. Substitution on the
indoline core of the products was next studied, with both
electron-withdrawing 5-Cl and electron-donating 6-OMe groups
incorporated to give products 29 and 30 in good yield (46–50%).
In all examples, analysis of the crude reaction product mixture
by 1H NMR spectroscopy revealed the formation of a number of
minor side products; however none of these were successfully
isolated or characterized. In each case only
a single
diastereoisomer was isolated, with products 24, 29 and 30 also
characterized by single crystal X-ray crystallographic analysis,
confirming the same relative configuration within each
product.[19,20]
Proposed Mechanism
Further studies sought to obtain insight into the mechanism of
this reaction. The synthesis of related fused ring systems has
been reported in the literature through purported [2+2]
cycloadditions via transient ketene intermediates.[21] In the
majority of these examples dehydrochlorination of an acid
chloride was utilized to generate the ketene in situ, followed by
cycloaddition to a pendant alkene to give carbocyclic and
oxygen-containing heterocyclic ring systems. Interception of a
similar mechanistic pathway could be envisaged in the current
study through base-promoted elimination of pivalic acid from the
in situ-generated mixed anhydride 31 (Scheme 6, Path A).[22]
This mechanism would be of particular interest considering
previous reports that suggest C(1)-ammonium enolate catalysis
most likely proceeds without the intermediacy of a ketene (see
Scheme 1b).[23] However, based on the relative nucleophilicity of
the pendant enamide, an ionic mechanism, either via ketene 32
(Scheme 6, Path B),[24] or through direct intramolecular addition
of the enamide to the mixed anhydride (Scheme 6, Path C),[25]
could also be considered. All these pathways could also be
initiated in the presence of a Lewis basic amine by conversion of
Yields calculated using mass of partially-purified enamide substrate used.
Structure representations of 24, 29 and 30 based on single crystal X-ray
crystallographic analysis. Majority of hydrogen atoms omitted for clarity.
the mixed anhydride to an acyl ammonium.[26] In pathways B and
C, the final cyclization could be classified as 4-enolendo-exo-trig,
which would be disfavored according to Baldwin’s rules.[27]
However formally-disfavored enolendo-cyclizations have been
proposed when zwitterionic intermediates are involved,[28] and
therefore cannot be completely ruled out as a possibility in this
case.
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10.1002/ejoc.201900326
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COMMUNICATION
Scheme 8. Proposed mechanism for the formation of indoline-cyclobutanone
fused products
Scheme 6. Possible mechanistic pathways for the formation of indoline-
cyclobutanone fused products 35 in the presence of i-Pr2NEt.
Conclusions
To provide insight into the potential for ketene generation, a
model substrate 36, bearing an unactivated alkene, was applied
under the standard conditions (Scheme 7). Reaction progress at
room temperature was monitored by 1H NMR spectroscopy.
Within two hours, 55% conversion to known cyclobutanone 37
was observed,[29] indicative of a [2+2] cycloaddition mechanism
involving a ketene. Although the alternate pathways cannot be
fully discounted for the formation of the indoline-cyclobutanone
fused products, this experiment does indicate the feasibility of
During investigations into a tertiary amine-catalyzed cyclization,
an unexpected process for generating novel indoline-
cyclobutanone derivatives was discovered serendipitously. This
intramolecular process was applicable for the diastereoselective
formation of a range of novel heterocyclic products, which may
prove useful intermediates in natural product synthesis or the
discovery of bioactive compounds. Based on literature
precedents and mechanistic investigations, the reaction is
proposed to proceed by an intramolecular [2+2] cycloaddition
involving an in situ generated ketene. Evidence for the formation
of a ketene from a mixed anhydride at room temperature
highlights the importance of remaining cognizant of this reactive
intermediate when developing enantioselective Lewis base-
catalyzed processes.[30]
Path A. This demonstration of ketene formation from
a
phenylacetic anhydride derivative at room temperature, in the
presence of pivaloyl chloride and i-Pr2NEt, also provides
instructive insight for practitioners of C(1)-ammonium enolate
catalysis.[23,26]
Acknowledgments
Scheme 7. Mechanistic probe for in situ generation of a ketene intermediate
We thank the EPSRC Centre for Doctoral Training in Critical
Resource Catalysis (CRITICAT, grant code EP/L016419/1,
R.M.N.) for funding. We thank the European Research Council
under the European Union’s Seventh Framework Programme
(FP7/2007–2013) ERC grant agreement no. 279850 (A.D.S.).
A.D.S. thanks the Royal Society for a Wolfson Research Merit
Award. We also thank the EPSRC UK National Mass
Spectrometry Service at Swansea.
Based on these studies, and the lack of enantioinduction in the
presence of a chiral Lewis base catalyst, a mechanism for the
formation of these novel indoline-cyclobutanone products can be
proposed (Scheme 8). Reaction of the acid substrate 38 with
pivaloyl chloride and i-Pr2NEt provides mixed anhydride 39,
which undergoes i-Pr2NEt-promoted elimination of pivalic acid to
give ketene 40. Intramolecular [2+2] cycloaddition between the
ketene and the pendant enamide then provides indoline-
cyclobutanone 41. The relative configuration of the isolated
product is consistent with diastereospecific [2+2] cycloaddition
involving only the (E)-enamide substrate. The (Z)-enamide may
isomerize or decompose under the reaction conditions, the latter
of which could partially account for the generally moderate yields
obtained. Alternatively the (Z)-enamide may undergo
diastereospecific [2+2] cycloaddition to give a diastereoisomer of
the product that differs in configuration at the C(2) position.
While this diastereoisomer was not observed, it may simply not
have been isolable, or may have undergone epimerization at
C(2) to give the isolated diastereoisomer 41.
Keywords: Lewis base catalysis • ketene • [2+2]-cycloaddition •
N-heterocycles • indoline-cyclobutanone
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10.1002/ejoc.201900326
European Journal of Organic Chemistry
COMMUNICATION
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Heterocycle Synthesis
Rifahath M. Neyyappadath, Mark D.
Greenhalgh, David B. Cordes,
Alexandra M. Z. Slawin, Andrew D.
Smith*
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A serendipitously-discovered intramolecular [2+2] cycloaddition process is reported
for the synthesis of novel indoline-cyclobutanone derivatives. The reaction is
proposed to proceed by Brønsted base-promoted elimination of pivalic acid from a
mixed anhydride to generate a ketene in situ.
Synthesis of Fused Indoline-
Cyclobutanone Derivatives via an
Intramolecular [2+2] Cycloaddition
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