Simple Aza -conjugate addition methodology for the synthesis of isoindole nitrones and 3,4-dihydroisoquinoline nitrones

Article abstract of DOI:10.1021/acs.orglett.5b00103

Aryl-aldehydes containing ortho-substituted α,β-unsaturated carboxylic acid derivatives react with hydroxylamine to afford reactive N-hydroxy-carbinolamine intermediates that undergo intramolecular aza-conjugate addition reactions to afford isoindole nitrones and 3,4-dihydroisoquinoline nitrones in good yield. Conditions have been developed to reduce these isoindole nitrones to their corresponding hydroxylamine, enamine, and amine derivatives. Isoindole nitrones react with dimethyl acetylenedicarboxylate (DMAD) via a [4 + 2]-cycloaddition/deamination pathway to afford substituted naphthalene derivatives, while 3,4-dihydroisoquinoline nitrones react with DMAD via a [1,3]-dipolar cycloaddition pathway to afford tricyclic heteroarenes.

Full text of DOI:10.1021/acs.orglett.5b00103

Letter
pubs.acs.org/OrgLett
Simple Aza-Conjugate Addition Methodology for the Synthesis of
Isoindole Nitrones and 3,4-Dihydroisoquinoline Nitrones
Lucy R. Peacock,† Robert S. L. Chapman,† Adam C. Sedgwick,† Mary F. Mahon,‡ Dominique Amans,§
and Steven D. Bull*,†
†Department of Chemistry, University of Bath, Bath, BA2 7AY, U.K.
‡Bath X-ray Crystallographic Suite, University of Bath, Claverton Down, Bath, BA2 7AY, U.K.
§Epinova Discovery Performance Unit, GSK, Gunnels Wood Road, Stevenage, Herts, SG1 2NY, U.K.
S
* Supporting Information
ABSTRACT: Aryl-aldehydes containing ortho-substituted α,β-
unsaturated carboxylic acid derivatives react with hydroxylamine
to afford reactive N-hydroxy-carbinolamine intermediates that
undergo intramolecular aza-conjugate addition reactions to afford
isoindole nitrones and 3,4-dihydroisoquinoline nitrones in good
yield. Conditions have been developed to reduce these isoindole
nitrones to their corresponding hydroxylamine, enamine, and amine derivatives. Isoindole nitrones react with dimethyl
acetylenedicarboxylate (DMAD) via a [4 + 2]-cycloaddition/deamination pathway to afford substituted naphthalene derivatives,
while 3,4-dihydroisoquinoline nitrones react with DMAD via a [1,3]-dipolar cycloaddition pathway to afford tricyclic
heteroarenes.
itrones are an important class of organic compound that
are traditionally prepared via oxidation of imines, amines,
give a N-hydroxy-carbinolamine intermediate 2 that is in
equilibrium with oxime 3. The N-hydroxy-amino functionality
of 2 then undergoes a 5-exo-trig aza-conjugate addition reaction
to afford bicyclic enolate intermediate 4. Elimination of water
from isoindoline 4 then occurs to afford nitrone 5 which
undergoes a series of tautomerization events (via N-hydroxy-2H-
isoindole 6) to afford the thermodynamically more stable nitrone
7a (Scheme 1).
A series of reactions were then carried out in an attempt to
provide evidence for this mechanistic rationale. First, it was found
that aldehyde 1a reacted with NH2OH·HCl, in the absence of
sodium acetate, to give the stable oxime 3, which only cyclized to
afford nitrone 7a on exposure to excess sodium acetate. We also
found that addition of N-methyl-hydroxylamine to a mixture of
aldehyde 1a and Et3N in water/THF at rt afforded N-methyl-
carbinolamine-N-oxide 8 (cf. intermediate 4) as a mixture of
diastereomers (Scheme 2a).
Although N-hydroxy-carbinolamine 2 could potentially afford
intermediate 4 via a reverse-Cope mechanism, these type of
intramolecular cyclization reactions are normally favored by
substrates containing relatively electron-rich alkenes.8 Further
evidence against a reverse-Cope reaction was obtained by reacting
styrene aldehyde 9 with NH2OH·HCl under basic conditions,
which cleanly afforded its corresponding oxime 10 (cf oxime 3),
with no evidence of any cyclic nitrone product being produced
(Scheme 2b). Furthermore, treatment of aldehyde 1a with O-
methyl-hydroxylamine resulted in clean formation of the nitrone
salt 11 (cf. intermediate 5), consistent with an aza-conjugate
N
and hydroxylamines using a variety of oxidants and catalysts.1 A
number of nonoxidative methods for their synthesis have also
been developed, including condensation of N-monoalkylated
hydroxylamines with carbonyl compounds2 or N-alkylation of
oximes using alkene derivatives.3 Nitrones are versatile substrates
for a wide range of reactions1 and are also useful as free radical
spin traps for electron paramagnetic resonance (EPR) studies on
biological systems.4 For example, the isoindole-derived nitrones
DMPO (5,5-dimethyl-pyrroline-N-oxide), TMINO (1,1,3-tri-
methyl-isoindole-N-oxide), and 3-TF-TMINO (1,1,3-trimethyl-
isoindole-N-oxide) have proven to be particularly useful for
detecting oxidative radical species in biological systems, due to
the improved stability of their derived radical adducts.5 3,4-
Dihydroisoquinoline derived nitrones have been employed as
synthetically versatile substrates for a range of reactions,1
including enantioselective [1,3]-dipolar cycloaddition and
nucleophilic addition reactions,6 as well as free radical trapping
agents for the treatment of stroke.7 Given this utility, we now
report efficient cyclization methodology for the synthesis of
isoindole nitrones and 3,4-dihydroisoquinoline nitrones that
contain carboxylate side chains that are potentially useful for
bioconjugation.
As part of a research program directed toward the synthesis of
novel heterocyclic ring systems for drug discovery and sensing
applications, we found that reaction of the aldehyde functionality
of α,β-unsaturated ester 1a with NH2OH·HCl and excess sodium
acetate (or Et3N) in water/EtOH at rt resulted in clean
formation of isoindole nitrone 7a in 78% yield. Under these
conditions, it is proposed that hydroxylamine reacts reversibly
with the aldehyde functionality of α,β-unsaturated ester 1a to
Received: January 12, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00103
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
cyclization reaction of 1a with hydroxylamine in the presence of
D2O resulted in a nitrone product 7a-d4 with 77% deuterium
incorporation α to its ester group and 64% deuterium
incorporation at its benzylic position (Scheme 2e). Furthermore,
treatment of unlabeled nitrone 7a with NaOAc in a 5:1 mixture
of EtOD/D2O also resulted in deuterium incorporation α to its
ester functionality and at its benzylic position. These results
clearly reveal the presence of a tautomeric equilibrium between 5
and 7a in solution (via 6) under basic conditions.10
Scheme 1. Reaction of the Aldehyde Functionality of α,β-
Unsaturated Ester 1a with Hydroxylamine To Afford Nitrone
7a
The conditions employed to carry out cyclization 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 −20 °C gave nitrone 7a in 91% yield. These optimal
conditions were then applied to the cyclization of a series of 19
α,β-unsaturated carboxylic acid derivatives 1b−t that gave their
corresponding nitrones 7b−t in 59−94% yields (Table 1).
Therefore, aryl-aldehydes 1b−h containing both electron-
donating and -withdrawing substituents cyclized cleanly to afford
their corresponding isoindole-nitrones 7b−h, with the structure
of fluorinated isoindole-nitrone 7g being confirmed by X-ray
crystallographic analysis (see Supporting Information (SI)).
Pyridine derived aryl-aldehyde ester 1i cyclized cleanly to afford
its expected isoindole nitrone 7i. However, the regioisomeric
pyridine substrate 1j afforded its tautomeric N-hydroxy-2H-
isoindole 7j isomer (cf. intermediate 6). Cyclization of alkene
substrates containing alternative electron-withdrawing groups
proceeded cleanly, with amide 1k, nitrile 1l, and thioester 1m
affording their corresponding isoindole-nitrones 7k−m in 59−
79% yield. Reaction of thioester 1m with hydroxylamine over an
extended 24 h period afforded the corresponding acid 7n in 68%
yield that is presumably formed from hydrolysis of the thioester
functionality of nitrone 7m in situ. The ketones 1o and 1p gave
their regioisomeric nitrone 7o and 7p respectively (cf. nitrones
11 and 13), while the γ-aryl-α,β-unsaturated esters 1q−t all
cyclized cleanly to afford the synthetically versatile 3,4-
dihydroisoquinoline nitrones 7q−t in good 77−92% yield.
All of the nitrones 7a−t proved to be stable when stored at 0
°C under nitrogen. However, they rapidly decomposed on
standing in air at rt. The potential synthetic utility of cyclic
nitrone 7a as a substrate for a series of reduction reactions was
then explored. Hydrogenation of the parent nitrone 7a over
palladium on charcoal in acidic methanol resulted in reduction/
deoxygenation to afford the corresponding isoindoline 14 in 69%
yield.11 Alternatively, treatment of 7a with samarium and cobalt
chloride in THF afforded enamine 15 in 39% yield,12 while
reduction of 7a with NaBH3CN in acidic methanol afforded N-
hydroxy-isoindoline 16 in 86% yield (Scheme 3).13
Scheme 2. Range of Reactions Employed To Probe the
Mechanism of the Cyclization Reaction of 1a To Afford
Nitrone 7a
Attempts to employ isoindole nitrone 7a as a substrate for a
range of known nitrone reactions (see SI) proved unsuccessful,1
affording either recovered starting material, nitrone products
from a competing reaction of their ester functionalities, or
colored polymeric material. We reasoned that this unusual
reactivity profile was likely to be due to the relatively unstable
isoindole nitrone 7a preferentially reacting via its N-hydroxy-2H-
isoindole tautomer 6.14 We therefore decided to investigate
whether 6 could be used as a diene component in a Diels−Alder
reaction with an appropriate dienophile.14 Isoindole nitrone 7a
was reacted with dimethyl acetylenedicarboxylate (DMAD) in
THF at rt, which resulted in a clean [4 + 2]-cycloaddition
reaction to afford an unstable bridged N-hydroxy-1,4-dihydro-
naphthalene-1,4-imine 17 (observed by 1H NMR spectroscopic
analysis). This unstable cycloadduct underwent facile deami-
addition reaction operating under these conditions (Scheme 2c).
All of these observations are consistent with ring closure being
initiated by conjugate addition of the sp3 N-atom of N-hydroxy-
carbinolamine 2, which is more nucleophilic than the sp2 N-atom
of oxime 3.9
Further support for the intermediacy of 5 in the formation of
nitrone 7a was obtained by treatment of aryl-aldehyde 12, with
hydroxylamine under basic conditions which cleanly afforded the
regioisomeric nitrone 13 (Scheme 2d). Indeed, carrying out the
B
DOI: 10.1021/acs.orglett.5b00103
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Synthesis of a Range of Nitrone Analogues 7a−t
a
b
Protocols for the synthesis of α,β-unsaturated esters 1a−1t are reported in the SI. Cyclization reaction carried out over a period of 24 h.
dihydroisoquinoline nitrone 7q reacted with DMAD via its
expected [1,3]-dipolar cycloaddition pathway, to afford dihydro-
isoxazole 20 as an inseparable 85:15 mixture of diastereomers in
83% yield.16 Repeating the reaction of nitrone 7q with DMAD in
toluene at reflux resulted in formation of tricyclic pyrrole 24 in
42% yield, which was also formed in 75% yield by treating
Scheme 3. Reduction of Nitrone 7a To Afford Amine 14,
Enamine 15, and Hydroxylamine 16
dihydroisoxazole 20 with DMAD in toluene at reflux.16
A
reasonable mechanism for formation of pyrrole 24 is shown in
Scheme 4b, whereby intramolecular aza-conjugate addition of
the nitrogen lone pair of dihydroisoxazole 20 first affords a
reactive aziridine intermediate 21. Aziridine 21 then undergoes
thermal ring opening to afford an azomethine ylide 22 that
participates in a second [1,3]-dipolar cycloaddition reaction with
DMAD to afford dihydropyrrole 23 that then eliminates a methyl
glyoxylate equivalent to afford tricyclic pyrrole 24.16
native aromatization (via elimination of a nitroxyl (HNO)
equivalent from N-oxide 18) on standing, to afford naphthyl
triester 19 in 87% yield (Scheme 4a).15 In contrast, 3,4-
C
DOI: 10.1021/acs.orglett.5b00103
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. (a) [4 + 2]-Cycloaddition Reactions of Isoindole 7a
with DMAD; (b) [1,3]-Dipolar Cycloaddition Reactions of
3,4-Dihydroisoquinoline 7q with DMAD
REFERENCES
■
(1) Feuer, H. Nitrile Oxides, Nitrones, and Nitronates in Organic
Synthesis: Novel Strategies in Synthesis, 2nd ed.; Wiley: NJ, 2008.
(2) (a) Knobloch, K.; Koch, J.; Keller, M.; Eberbach, W. Eur. J. Org.
Chem. 2005, 2715. (b) Bogevig, A.; Poulsen, T. B.; Zhuang, W.;
Jorgensen, K. A. Synlett 2003, 1915. (c) Yang, D.; Micalizio, G. C. J. Am.
Chem. Soc. 2011, 133, 9216.
(3) (a) Armstrong, P.; Grigg, R.; Heaney, F.; Surendrakumar, S.;
Warnock, W. J. Tetrahedron 1991, 47, 4495. (b) Grigg, R.; Dorrity, M. J.;
Heaney, F.; Malone, J. F.; Rajviroongit, S.; Sridharan, V.;
Surendrakumar, S. Tetrahedron 1991, 47, 8297. (c) Grigg, R.; Heaney,
F.; Markandu, J.; Surendrakumar, S.; Thornton-Pett, M.; Warnock, W. J.
Tetrahedron 1991, 47, 4007. (d) Grigg, R.; Heaney, F.; Surendrakumar,
S.; Warnock, W. J. Tetrahedron 1991, 47, 4477.
(4) Floyd, R. A. Proc. Soc. Exp. Biol. Med. 1999, 222, 236.
(5) (a) Bottle, S. E.; Hanson, G. R.; Micallef, A. S. Org. Biomol. Chem.
2003, 1, 2585. (b) Bottle, S. E.; Micallef, A. S. Org. Biomol. Chem. 2003,
1, 2581. (c) Hatano, B.; Sato, H.; Ito, T.; Ogata, T. Synlett 2007, 2130.
(6) (a) Carmona, D.; Lamata, M. P.; Viguri, F.; Rodriguez, R.; Oro, L.
A.; Lahoz, F. J.; Balana, A. I.; Tejero, T.; Merino, P. J. Am. Chem. Soc.
2005, 127, 13386. (b) Ukaji, Y.; Kenmoku, Y.; Inomata, K. Tetrahedron:
Asymmetry 1996, 7, 53.
(7) (a) Fevig, T. L.; Bowen, S. M.; Janowick, D. A.; Jones, B. K.;
Munson, H. R.; Ohlweiler, D. F.; Thomas, C. E. J. Med. Chem. 1996, 39,
4988. (b) Thomas, C. E.; Bernardelli, P.; Bowen, S. M.; Chaney, S. F.;
Friedrich, D.; Janowick, D. A.; Jones, B. K.; Keeley, F. J.; Kehne, J. H.;
Ketteler, B.; Ohlweiler, D. F.; Paquette, L. A.; Robke, D. J.; Fevig, T. L. J.
Med. Chem. 1996, 39, 4997.
(8) (a) Cooper, N. J.; Knight, D. W. Tetrahedron 2004, 60, 243.
(b) Peng, X.; Tong, B. M. K.; Hirao, H.; Chiba, S. Angew. Chem., Int. Ed.
2014, 53, 1959.
(9) For reports where nitrogen anions of amino intermediates derived
from aldehyde 1a undergo intramolecular aza-conjugate addition
reactions to afford chiral isoindolines, see: (a) Takizawa, S.; Inoue, N.;
Hirata, S.; Sasai, H. Angew. Chem., Int. Ed. 2010, 49, 9725. (b) Fustero,
́ ́ ́
S.; Moscardo, J.; Sanchez-Rosello, M.; Rodríguez, E.; Barrio, P. Org. Lett.
2010, 12, 5494. (c) Enders, D.; Narine, A. A.; Toulgoat, F.; Bisschops, T.
Angew. Chem., Int. Ed. 2008, 47, 5661.
(10) Bender, C. O.; Bonnett, R.; Smith, R. G. J. Chem. Soc. C 1970,
1251.
(11) Racine, E.; Bello, C.; Gerber-Lemaire, S.; Vogel, P.; Py, S. J. Org.
In conclusion, we have shown that aryl-aldehydes containing
ortho-substituted α,β-unsaturated carboxylic acid fragments react
with hydroxylamine via a tandem nucleophilic addition−aza-
conjugate addition−elimination pathway to afford a series of 20
cyclic nitrones.17 These nitrones can be reduced to their
corresponding amine, enamine, and hydroxylamine derivatives
and used as substrates in [4 + 2]- and [1,3]-dipolar cycloaddition
reactions for the synthesis of naphthalenes and tricyclic
heteroarenes.
Chem. 2009, 74, 1766.
(12) Zhang, J. M.; Zhang, Y. M. Chin. Chem. Lett. 2001, 12, 945.
(13) Maeda, H.; Kraus, G. A. J. Org. Chem. 1997, 62, 2314.
(14) Bonnett, R.; Brown, R. F. C.; Smith, R. G. J. Chem. Soc., Perkin
Trans. 1 1973, 1432.
(15) For a related report on Diels−Alder reactions of 2H-isoindoles
with DMAD to afford [4 + 2]-cycloadducts that underwent deaminative
aromatization to afford naphthalenes on treatment with a strong
oxidizing agent, see: Tong, B. M. K.; Hui, B. W-Q; Chua, S. H.; Chiba, S.
Synthesis 2011, 3552.
(16) See: Huisgen, R.; Niklas, K. Heterocycles 1984, 22, 21.
(17) For other hydroxylamine mediated intramolecular cyclization
reactions of aldehydes containing electron-deficient alkenes that may
also proceed via aza-conjugate addition reactions of N-hydroxy-
carbinolamine intermediates, see: (a) Hall, A.; Meldrum, K. P.;
Therond, P. R.; Wightman, R. H. Synlett 1997, 123. (b) Argyropoulos,
N. G.; Panagiotidis, T. D.; Gallos, J. K. Tetrahedron: Asymmetry 2006, 17,
829. (c) Ishikawa, T.; Tajima, Y.; Fukui, M.; Saito, S. Angew. Chem., Int.
Ed. Engl. 1996, 35, 1863.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectral data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: s.d.bull@bath.ac.uk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the EPSRC (L.R.P. and A.C.S.), GSK (CASE award to
L.R.P.), and the EPSRC Doctoral Training Centre in Sustainable
Chemical Technologies at the University of Bath (R.S.L.C.) for
funding.
D
DOI: 10.1021/acs.orglett.5b00103
Org. Lett. XXXX, XXX, XXX−XXX