Aza-Conjugate Addition Methodology for the Synthesis of N-Hydroxy-isoindolin-1-ones

Article abstract of DOI:10.1021/acs.orglett.6b00261

Aryl-aldehydes containing ortho-substituted propiolate fragments react with hydroxylamine to afford carbinolamine intermediates that undergo intramolecular aza-conjugate addition reactions to afford N-hydroxy-2.3-dihydro-isoindolin-1-ones that can be redu

Full text of DOI:10.1021/acs.orglett.6b00261

Letter
pubs.acs.org/OrgLett
Aza-Conjugate Addition Methodology for the Synthesis of
N‑Hydroxy-isoindolin-1-ones
Santiago Royo,‡ Robert S. L. Chapman,† Alisia M. Sim,† Lucy R. Peacock,† and Steven D. Bull*,†
†Department of Chemistry, University of Bath, Bath, BA2 7AY, U.K.
‡Departament de Química Inorgan
ica i Organica, Universitat Jaume I, Castello, Spain
̀ ̀ ́
S
* Supporting Information
ABSTRACT: Aryl-aldehydes containing ortho-substituted
propiolate fragments react with hydroxylamine to afford
carbinolamine intermediates that undergo intramolecular
aza-conjugate addition reactions to afford N-hydroxy-2.3-
dihydro-isoindolin-1-ones that can be reduced to their
corresponding isoindolin-1-ones and isoindoles.
Scheme 1. (a) Reaction of Aryl Aldehydes 1 with
Hydroxylamine Affords Cyclic Nitrones 2; (b) Reaction of
Aryl Aldehydes 3 with Hydroxylamine Affords N-Hydroxy-
isoindolin-1-ones 4
yclic hydroxamic acids are an important class of
Ccompounds that possess a wide range of biological
activity, including compounds that exhibit potent antimalarial,1
prolyl-4-hydroxylase,2 α-glucosidase, and N-methyl-aspartate
inhibitory actions.3 The biological activity of cyclic hydroxamic
acids is often due to their ability to chelate to metal ions such as
iron and zinc,2,4 which has enabled ion transport and HIV-1
integrase inhibitors to be developed.4a,c There are a number of
routes available for the synthesis of these cyclic hydroxamic
acids, including zinc/palladium catalyzed reduction of nitro
groups to afford hydroxylamine intermediates that cyclize onto
acid derivatives.3b,c,5 A number of nonreductive methods for
their synthesis have also been developed, including approaches
based on photorearrangement of nitronate anions,6 ring-
expansion reactions of acyloxy nitroso compounds derived
from cyclic ketones,7 ene cyclization reactions of unsaturated
N-acyl-nitroso species,8 intramolecular cyclization of enolates
onto N-benzyloxy-carbamates fragments,9 base catalyzed
cyclization reactions of 2-alkynylphenylhydroxamic acids,10
conjugate addition of hydroxylamine derivatives to α,β-
unsaturated acid derivatives,11 and selenium-mediated cycliza-
tion of acyclic unsaturated hydroxamic acids.12 Given their
synthetic utility and wide ranging biological activity, we now
report efficient aza-conjugate addition methodology for the
synthesis of N-hydroxy-isoindolinones and their conversion
into their corresponding isoindolin-1-one and isoindole
skeletons.
We have previously reported that treatment of aryl-aldehydes
1 containing ortho-substituted α,β-unsaturated carboxylic acid
derivatives with hydroxylamine affords reactive N-hydroxy-
carbinolamine intermediates that undergo intramolecular aza-
conjugate addition reactions to afford isoindole and 3,4-
dihydroisoquinoline nitrones 2 in good yield (Scheme 1a).13
Consequently, we decided to investigate what would occur if
these cyclization conditions were applied to the corresponding
propiolate esters 3 and now report herein that their reaction
with hydroxylamine affords N-hydroxy-isoindolin-1-ones 4 in
good yield (Scheme 1b).
A robust five-step synthesis of 2-propiolate benzaldehydes
3a−g and 8 was first devised, commencing with copper-free
Sonogashira coupling reactions between 2-bromobenz-
aldehydes 5a−g and (triisopropylsilyl)acetylene to afford the
TIPS protected 2-alkynyl benzaldehydes 6a−g in 83−91%
yield. Acetal protection of aldehydes 6a−g with 1,3-propane-
diol, followed by silyl deprotection using tetrabutylammonium
fluoride (TBAF), resulted in a series of alkynes 7a−g in 81−
99% yield. These alkynes were then deprotonated with n-BuLi
in THF at −78 °C to afford their corresponding alkynyl anions
that were reacted with methyl chloroformate, followed by acid
catalyzed acetal deprotection to afford the desired 2-propiolate
benzaldehydes 3a−g in 45−59% yield over the five steps
(Scheme 2). Reaction of the propargylic alkynyl anion of 7c
with methyl chloroformate, followed by base-catalyzed ester
hydrolysis, gave its parent acid. This acid then underwent
Received: January 26, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00261
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Letter
Scheme 2. Synthesis of Cyclization Substrates 3a−g and 8
Table 1. Synthesis of N-Hydroxy-isoindolin-1-ones 3a−g and
8
Scheme 3. Proposed Reaction of the Aldehyde Functionality
of Methyl Propiolate 3a with Hydroxylamine To Afford
Hydroxamic Acid 4a
a
5 equiv of Cs2CO3 added to facilitate cyclization.
mechanism to explain the formation of 4a involves initial
reversible addition of hydroxylamine to its aldehyde function-
ality to afford N-hydroxy-carbinolamine 9 that then undergoes
an aza-conjugate addition reaction to afford a bicyclic allenyl
enolate intermediate 10. Enolate protonation of 10 then occurs
to afford a N-hydroxy-enamine intermediate 11, which is then
protonated to afford nitrone 12 that undergoes water-mediated
tautomerization (via oxime 13) to afford the hydroxamic acid
functionality of N-hydroxy-isoindolin-1-one 4a (Scheme 3).
DCC-mediated amide bond coupling with aniline, followed by
acid-catalyzed acetal hydrolysis to afford amide 8.
Reaction of the aldehyde functionality of methyl-propiolate
3a with 1.1 equiv of a 50% aqueous solution of hydroxylamine
at room temperature resulted in an unexpected cyclization
reaction to afford N-hydroxy-isoindolin-1-one 4a. A reasonable
B
DOI: 10.1021/acs.orglett.6b00261
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Scheme 4. Synthesis of Isoindolin-1-ones 15a−d
Scheme 6. Synthesis of 6-Fluoro Analogue of PD172938
Scheme 5. Synthesis of 5-Fluoro-isoindole 18
RuCl3·3H2O and 30 mol % Zn−Cu couple in EtOH at 90 °C
for 24 h,16 which gave the transesterified ethyl esters of
isoindolin-1-ones 15a and 15b in acceptable 51−66% yields,
respectively. Alternatively, stepwise treatment of electron-poor
N-hydroxy-isoindolin-1-ones 4c−d with 1.5 equiv of diethyl
phosphorocyanidate and 2 equiv of Et3N in THF for 30 min at
room temperature gave their corresponding phosphate diester,
which were immediately reduced with 4 equiv of samarium
iodide in THF for 1 h,17 to give isoindolin-1-ones 15c−e in
acceptable 51−71% yields (Scheme 4). Finally, treatment of 5-
fluoro-isoindolin-1-one 15d with (Boc)2O and DMAP afforded
N-Boc-5-fluoro-isoindolin-1-one 16 that was reduced via
treatment with LiEt3BH to give a N-Boc-carbinolamine
intermediate 17 that was treated with BF3·OEt3 and Et3SiH,18
to afford the desired 5-fluoro-isoindole skeleton of N-Boc-β-
amino ester 18 in 58% yield over two steps (Scheme 5).
Isoindoline-2-ones such as PD172938 23 (R = H) have been
shown to be potent antagonists for dopamine D4 receptors, and
their use as potential treatments for schizophrenia has been
investigated.19 Consequently, it was decided to employ our
cyclization methodology to prepare a 6-fluoro-isoindolin-1-one
analogue 22 (R = F) using the protocol shown in Scheme 6.
Therefore, aldehyde 3g was treated with hydroxylamine under
our standard conditions to afford N-hydroxy-6-fluoro-isoindo-
lin-1-one 4g in 66% yield, whose phosphate ester was then
reduced using samarium iodide to afford 6-fluoro-isoindolin-1-
one 15e in 72% yield. Ester 15e was then reduced to its
corresponding alcohol 19 using LiBH4 in 67% yield that was
then reacted with Et3N, DMAP, and tosyl chloride to afford O-
tosyl-6-fluoro-isoindolinone 20 in 70% yield. Nucleophilic
substitution of tosylate 20 using N-aryl-piperidine 21 under
Repeating the cyclization reaction of methyl-propiolate 3a with
hydroxylamine at −20 °C resulted in precipitation of a
crystalline product that was isolated and found to have
spectroscopic data consistent with the structure of nitrone
intermediate 12, which decomposed on standing to afford N-
hydroxy-isoindolin-1-one 4a.
The conditions used to carry out the cyclization reaction of
aldehyde 1a were then optimized by screening different bases,
solvents, and sources of hydroxylamine, which enabled us to
identify that use of 1.1 equiv of hydroxylamine (50% solution in
water) in THF at rt for 30 min could be employed to afford N-
hydroxy-isoindolin-1-one 4a in 70% yield. These optimal
conditions were then applied to the cyclization of six further
propiolate derivatives 3b−f and 8 that contain both electron-
donating and -withdrawing substituents, which all cyclized
cleanly to give their corresponding cyclic hydroxamic acids 4b−
f and 14 in 51−95% yields (Table 1).
The parent isoindolin-2-one and isoindole ring systems occur
as fragments of many natural products.14 Therefore, they may
be considered to be privileged structures for drug discovery
applications.14c,d Consequently, investigation was initiated to
identify conditions that would enable cleavage of the N−O
bond of our N-hydroxyisoindolin-1-ones. A range of known
N−O bond cleavage conditions were screened for this
purpose,15 with the best results being obtained for electron-
rich N-hydroxy-isoindolin-1-one 4a and 4b using 5 mol %
C
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1502.
In conclusion, we have shown that aryl-aldehydes 3
containing ortho-substituted propiolate fragments react with
hydroxylamine via a nucleophilic addition-aza-conjugate
addition pathway to afford a series of cyclic N-hydroxy-
isoindolin-1-ones 4 that may be reduced to their parent
isoindolin-1-one or isoindole skeletons as required.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00261.
Experimental procedures and spectral data for all new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: s.d.bull@bath.ac.uk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Generalitat Valenciana for a postdoctoral research
grant under the VALi+d Program (S.R), the EPSRC (L.R.P.),
and the EPSRC Centre for Doctoral Training in Sustainable
Chemical Technologies at the University of Bath (R.S.L.C.) for
funding.
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DOI: 10.1021/acs.orglett.6b00261
Org. Lett. XXXX, XXX, XXX−XXX