Benzoazepine-Fused Isoindolines via Intramolecular (3 + 2)-Cycloadditions of Azomethine Ylides with Dinitroarenes

Article abstract of DOI:10.1021/acs.orglett.9b01580

Aminobenzaldehydes bearing a pendant 3,5-dinitrophenyl group react thermally with N-substituted α-amino acids to form unprecedented benzoazepine-fused isoindolines. The reaction proceeds via a dearomatization/rearomatization sequence involving an intramolecular (3 + 2)-cycloaddition between the in situ formed azomethine ylide and the dinitroarene. Various glycine derivatives are tolerated as well as branched substrates based on cyclic, α-mono-, and α,α-disubstituted amino acids, giving single diastereomers in many cases. The method is scalable and gives products with a nitro group ready for further manipulation.

Full text of DOI:10.1021/acs.orglett.9b01580

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Benzoazepine-Fused Isoindolines via Intramolecular (3 + 2)-
Cycloadditions of Azomethine Ylides with Dinitroarenes
Steven M. Wales,†,⊥ Daniel J. Rivinoja,†,⊥ Michael G. Gardiner,‡ Melissa J. Bird,† Adam G. Meyer,§
John H. Ryan,§ and Christopher J. T. Hyland*,†
†School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia
‡School of Natural Sciences − Chemistry, University of Tasmania, Hobart, Tasmania 7001, Australia
§CSIRO Biomedical Manufacturing, Ian Wark Laboratory, Bayview Avenue, Clayton, Victoria 3168, Australia
S
* Supporting Information
ABSTRACT: Aminobenzaldehydes bearing a pendant 3,5-
dinitrophenyl group react thermally with N-substituted α-
amino acids to form unprecedented benzoazepine-fused
isoindolines. The reaction proceeds via a dearomatization/
rearomatization sequence involving an intramolecular (3 + 2)-
cycloaddition between the in situ formed azomethine ylide
and the dinitroarene. Various glycine derivatives are tolerated as well as branched substrates based on cyclic, α-mono-, and α,α-
disubstituted amino acids, giving single diastereomers in many cases. The method is scalable and gives products with a nitro
group ready for further manipulation.
Conversely, Starosotnikov demonstrated that N-methylglycine
ngaging π-bonds of benzene derivatives in cycloaddition
Eprocesses is a powerful approach to generate poly(hetero)- reacted thermally with formaldehyde in the presence of
cyclic compounds from readily available materials.1 Prominent
polynitrobenzenes to give isoindoles (e.g., 2) after rear-
omatization and oxidation of the initial cycloadducts (Scheme
examples of complexity-building reactions of benzene deriva-
tives that proceed through (formal) cycloadditions include
cyclopropanations,2 trimethylenemethane cycloadditions,3 (4 +
3)-cycloadditions,4 (hetero)-Diels−Alder reactions,5 and pho-
tochemical variants.6 A 1,3-dipolar cycloaddition between an
azomethine ylide (AMY)7 and a benzene-embedded dipolar-
ophile is another efficient strategy for arene functionalization,
providing access to isoindoline- or isoindole-containing
structures.8,9 The unique LUMO-lowering effect of the nitro-
substituent has proven particularly effective in opening up this
reactivity mode to common arene feedstocks (e.g., benzene,
indole).10 For example, Piettre and Chataigner reported efficient
cycloadditions of a symmetrical N-benzyl AMY with (hetero)-
arenes containing at least one nitro (or ester) substituent, giving
mono- or bispyrrolidino adducts such as 1 (Scheme 1a).11
1b).12
Although these developments (Scheme 1) demonstrate the
potential of generating isoindoline (or isoindole) heterocycles
through 1,3-dipolar cycloaddition of nonstabilized AMYs with
electron-deficient benzene derivatives, the scope of accessible
product types remains to be fully explored. This is especially the
case for scarcely investigated intramolecular AMY−arene
cycloadditions,13,14 which present untapped opportunities to
access more highly substituted isoindoline frameworks and to
improve selectivity for a single cycloaddition to the benzene ring,
where multiple additions11,15 are undesired. Carefully designed
intramolecular cycloaddition systems could therefore afford a
more controlled process, while simultaneously providing novel
polycyclic heterocycles. To be synthetically useful, such tethered
substrates should be easily prepared from commercially available
materials. We therefore designed readily prepared ortho-
heterobenzaldehydes tethered to a nitrophenyl group as
substrates to investigate in controlled, intramolecular AMY−
arene cycloadditions (Scheme 2).
Scheme 1. Exemplary Previous Work
Thermal condensation of aldehyde 3 with N-substituted α-
amino acids would be expected to generate dipole 4, which was
anticipated to undergo a regioselective, dearomatizing (3 + 2)-
cycloaddition with the pendant nitroarene to generate cyclo-
adduct 5. Rearomatization under thermal conditions10a,b,12,15a
would give the desired tetracycle 6.
Received: May 5, 2019
© XXXX American Chemical Society
A
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the amino acid to 5.0 equiv, all of which returned lower yields
than the reaction conditions noted in Table 1.
Scheme 2. Reaction Design Plan
In addition to the clear benefit in terms of reactivity observed
with the symmetrical and doubly activated 3,5-dinitrophenyl
derivative (Table 1, entry 3), the nitro group retained in the
product (12a) represented a potentially valuable handle for
downstream derivatization. Therefore, to assess the electronic
and steric effect of benzaldehyde substitution, a series of N-tosyl-
2-aminobenzaldehydes tethered to 3,5-dinitrobenzene (9b−k)
were prepared and treated with Bn-Gly-OH·HCl under the
standard reaction conditions (Scheme 3a). As with test substrate
a
Scheme 3. Scope of Benzaldehydes
As well as our interest in investigating the reactivity of α-
substituted amino acids in this study (where R3 and/or R4 ≠ H,
Scheme 2), the concomitant formation of the benzoazepine ring
system in 6 (where X = NR) during the cycloaddition process
was compelling from a structural standpoint.16 The 1-
benzoazepine skeleton features in a range of bioactive molecules
including agonists of N-methyl-D-aspartate17 and Vasopressin
V2 receptors.18 Isoindolines are also highly privileged motifs,
featured in a range of bioactive molecules.19 Therefore, a new
chemical entity (6) combining these two pharmacophores
would be potentially of high importance.
Initially, three test substrates (7−9a) with a tosyl-protected
amino linker were examined with variations in substitution at C-
5 of the pendant 3-nitroarene (Table 1). These aldehydes were
a
Table 1. Initial Results
a
Reactions performed on a 0.10 mmol scale. Yields are of isolated
b
products. A similar result was obtained using 2.0 equiv of N-
methylglycine (freebase) and 1.5 equiv of NEt3 for 8 h.
b
b
entry
R
product
time (h)
conv (%)
yield (%)
c
Corresponding isoindole (12j′) was also isolated in 12% yield.
d
1
2
3
H (7)
F (8)
NO2 (9a)
10
11
12a
24
24
2
79
89
100
<5
<5
Performed on a 0.07 mmol scale. Reaction time was 3 h.
c
74
9a, these reactions required ≤2 h to reach completion in all
cases. Substrates with methyl and methoxy substitution at C-5
reacted smoothly, giving 12b and 12c in 80 and 72% yields,
respectively. Systematic evaluation of halogens at C-5 with
increasing electronegativity resulted in slight incremental
decreases in yield (12d−f: 68−63%). Benzaldehydes bearing
chlorine at the para-position (C-4) or adjacent to the
sulfonamide (C-3) were also amenable to the cycloaddition,
giving 12g and 12h in 56 and 71% yields, respectively. In
contrast, reaction of Bn-Gly-OH·HCl (or Me-Gly-OH) with a 6-
chloro substrate failed to produce 12i, leading only to
decomposition, likely due to steric incompatibility of a C-6
substituent with the N-substituent of the amino acid. A
mesomerically electron-withdrawing ester at C-4 had a
detrimental effect on the efficiency of the process (12j: 38%),
whereas cycloaddition with a para-electron-donating morpho-
lino substituent gave 12k in moderate yield (59%).
a
b
Performed on a 0.10 mmol scale. Determined by 1H NMR
c
spectroscopy with mesitylene as the internal standard. Isolated yield.
each treated with Bn-Gly-OH·HCl under typical conditions to
promote AMY formation,20 along with NEt3 to neutralize HCl
and any nitrous acid formed by rearomatization. The depend-
ency of product formation on the pendant arene substitution
(R) quickly became apparent: whereas substrates 7 and 8
bearing mononitro or fluoro/nitro activating groups, respec-
tively, decomposed slowly and gave no traceable products
(entries 1 and 2),21a the use of dinitro precursor 9a gave the
corresponding rearomatized cycloadduct 12a in 74% isolated
yield after 2 h (entry 3). Here, the only observed side product
derived from 9a was a trace of the corresponding isoindole
oxidized form of 12a, which was easily removed during
purification.21b Encouraged by this result, we examined the
effect of modifications to the reaction conditions including
variations in temperature (80 or 120 °C), alternative heating via
microwave at 100 °C, or increasing the relative stoichiometry of
Linkers (“X”) other than the N-Ts group were also briefly
examined (Scheme 3b). The sulfonamide group could be
successfully replaced with a benzoyl group, albeit at the expense
B
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of chemical yield (12l vs 12a). Additionally, we demonstrated
that an oxygen linker was feasible for the cycloaddition, isolating
cyclic ether 12m in a low, but repeatable, 25% yield.22,23
The scope of the cycloaddition with respect to N-substituted
α-amino acids was investigated using 9a as a model aldehyde,
targeting a range of derivatives 12n−z,aa (Scheme 4). Reaction
times for full consumption of 9a varied considerably (1−68 h)
and were correlated to the degree of α-substitution. N-PMB and
N-Me-glycine derivatives gave 12n and 12o in yields comparable
to those of Bn analogue 12a. α-Substituted N-Bn and/or N-Me
amino acids bearing Bn, Ph, Me, and i-Pr α-groups (R3) were
successful, giving moderate yields of 12p−u (44−56%) with a
general preference for the cis diastereomer; the degree of cis-
diastereoselectivity for these compounds (12p−u) was depend-
ent on both the N-substituent (R2) and the side chain (R3). For
example, whereas products 12q, 12t, and 12u (derived from α-
alkyl, N-Me amino acids) were obtained exclusively as cis-
diastereomers, α-substitution with a Ph group resulted in a
significant decrease in diastereoselectivity (12s: cis/trans =
1.7:1). Comparison of results for 12p and 12q obtained from N-
Bn- and N-Me-phenylalanine, respectively, showed a decrease in
cis-diastereoslectivity for the N-Bn substrate. N-Bn-α-Ph-glycine
was the only chiral amino acid that reacted to give product 12r
with essentially no diastereochemical enrichment (crude dr
[trans/cis] = 1.1:1). The only amino acid surveyed that did not
react productively was N-Me-histidine (12v).
α,α-Disubstituted amino acids were also amenable to the
cycloaddition (Scheme 4), as demonstrated with geminal
dimethylated products 12w and 12x, as well as the cis-enriched
α,α-Me-Ph derivative 12y (38−55% yields). Finally, the reaction
was extended to cyclic amino acids including proline and
thiaproline to give pentacyclic products 12z and 12aa as
exclusive trans stereoisomers.
a b
,
Scheme 4. Scope of Amino Acids
The relative stereochemistry of products 12q, 12s (major),
12z, and 12aa were established by X-ray crystallography
(Scheme 4 and Supporting Information). As expected,
representative product 12q of known cis-stereochemistry gave
a NOE correlation between the methine hydrogens on the fused
isoindoline ring system. The analogous NOE correlations
between methine hydrogens were also observed for 12p
(major), 12t, and 12u and similarly between the methine
hydrogen and C-methyl group of 12y (major). These
compounds were therefore assigned as cis-stereoisomers.
Previous computational studies have concluded that cyclo-
additions of nonstabilized AMYs and nitroarenes occur through
an irreversible, concerted process.11b It is also known that
nonstabilized AMYs form from α-amino acids via stereospecific
decarboxylation of oxazolidinone intermediates and that the
derived AMYs can undergo isomerization before cycloaddition
in the absence of highly reactive dipolarophiles (e.g.,
maleimides).24 Based on those studies,11b,24 the divergent
diastereoselectivity of the current cycloaddition can be
rationalized by considering the preferred geometry of the dipole
undergoing the cycloaddition (Figure 1). The predominant cis-
Figure 1. Proposed reactive ylide geometries.
a
Reactions performed on a 0.10 mmol scale. Yields are of isolated
b
products. Diastereomeric ratios were determined by 1H NMR
spectroscopy. Isolated samples are enriched in the same epimers as
stereoselectivity observed with acyclic amino acids presumably
arises from reaction of a W-shaped ylide 4a. When switching
from N-Me to N-Bn amino acids, we believe that steric
interactions between R2 and R3 become more apparent, causing
partial adoption of a reactive S-shaped anti-configuration 4a′,
which results in a greater relative degree of trans isomer
formation. This effect appears to be more pronounced when a
Ph group occupies R3, regardless of R2, but we cannot rule out
nonsteric interactions (e.g., Ph-nitroarene π-stacking) playing a
role. Due to geometrical constraints, pentacyclic trans products
the crude mixtures. The relative configurations of the major epimers
c
are shown. Using 2 equiv of amino acid freebase and 1.5 equiv of
d
NEt3. Isolated with 5 mol % of the corresponding isoindole 12o′.
e
Relative configuration determined by NOE NMR spectroscopy.
f
Isolated with ∼10 mol % of an unknown side product.
g
Diastereomers were partially separated. Yield and dr represent that
h
1
of the combined isolates. Relative configuration determined by H
NMR spectral comparison with 12s and 12y. See the Supporting
i
Information. Using 2.0 equiv of Me-His-OH·2HCl and 5.5 equiv of
j
NEt3. Isolated with 10 mol % of the corresponding isoindole 12z′.
C
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12z and 12aa must arise from the cycloaddition of the
alternative S-shaped anti-configured ylide 4b; this trans-
diastereoselectivity is consistent with previous reports25 of
both intra- and intermolecular cycloadditions with analogous
AMYs derived from cyclic substrates (see the Supporting
Information for further illustrations).26
To demonstrate the scalability of the current method, the
known sulfonamide 13 was alkylated with commercially
available 3,5-dinitrobenzyl chloride on a gram scale to provide
aldehyde 9b (79%), which underwent reaction with Bn-Gly-
OH·HCl in 2 h to give 1.40 g of 12b (68%), without any
modifications to the standard conditions (Scheme 5). Notably,
potential of intramolecular, dearomatizing cycloadditions in
the formation of complex heterocyclic systems.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b01580.
Experimental procedures, characterization data, and
NMR spectra (PDF)
Accession Codes
CCDC 1911869−1911872 and 1911874−1911875 contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
Scheme 5. Larger-Scale Synthesis and Manipulations
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chris_hyland@uow.edu.au.
ORCID
Steven M. Wales: 0000-0003-0637-4225
Michael G. Gardiner: 0000-0001-6373-4253
Christopher J. T. Hyland: 0000-0002-9963-5924
Author Contributions
⊥S.M.W. and D.J.R. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The CSIRO, The University of Wollongong, and ARC
Discovery Project DP180101332 are acknowledged for
generous funding of this research.
REFERENCES
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(21) (a) The O-linked substrate, 2-((3,5-bis(trifluoromethyl)benzyl)
oxy)benzaldehyde was also investigated but under the same conditions
gave recovered starting material. (b) The ratios of the isoindoline/
isoindole (12/12′) in all crude samples directly after workup were
quantified by 1H NMR spectroscopy and are listed in the Supporting
Information. In one case, an isoindole side product (12j′) was isolated
in 12% yield and fully characterized.
(22) Attempts to optimize the yield of 12m by solvent screening
(THF, MeCN, DCE; each at 80 °C) or using other bases (DBU,
pyridine, DABCO) were unsuccessful. Two additional O-tethered
products were prepared in 23 and 15% yield from the reaction of
sarcosine and 2-((3,5-dinitrobenzyl)oxy)-5-methylbenzaldehyde or 5-
bromo-2-((3,5-dinitrobenzyl)oxy)benzaldehyde; see the Supporting
Information.
(23) Formation of 12m was monitored by reverse-phase LC-MS at
120 and 80 °C to attempt detection of the dearomatized cycloadduct
5m. Along with clear peaks for the aromatized cycloadduct and starting
material, a small peak with mass corresponding to 5m could be
observed, lending tentative support to the proposed mechanism in
Scheme 2 and the short lifetime of intermediate 5 (this species could
not be isolated by chromatography). It should be noted that the
azomethine ylide 4m has the same mass as 5m; however, this
(14) For rare examples of intramolecular (3 + 2) AMY−(hetero)arene
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J.; Heathcock, C. H. Intramolecular 1,3-Dipolar Cycloaddition of
Stabilized Azomethine Ylides to Unactivated Dipolarophiles. J. Org.
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Intramolecular 1,3-Dipolar Cycloadditions to a Furan Ring. Chem. Lett.
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Dicarboxylate. Inter- and Intramolecular Double 1,3-Dipolar Cyclo-
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(15) (a) Bastrakov, M. A.; Fedorenko, A. K.; Starosotnikov, A. M.;
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Substituted 3,5-Dinitropyridines and N-Methyl Azomethine Ylide.
Chem. Heterocycl. Compd. 2019, 55, 72−77. (b) Bastrakov, M. A.;
E
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Organic Letters
Letter
azomethine ylide might not be expected to be stable under aqueous
HPLC conditions.
(24) Grigg, R.; Idle, J.; McMeekin, P.; Vipond, D. The
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Dipole Formation. J. Chem. Soc., Chem. Commun. 1987, 49−51.
(25) (a) Grigg, R.; Surendrakumar, S.; Thianpatanagul, S.; Vipond, D.
The Decarboxylative Route to Azomethine Ylides. Stereochemistry of
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Dimerization of Cinnamaldehydes via 1,3-Dipolar Cycloaddition
Reaction with Azomethine Ylides. A Rapid Access to Highly
Functionalized Hexahydro-1H-Pyrrolizine. Tetrahedron Lett. 2008,
49, 5480−5483. (c) Bakthadoss, M.; Kannan, D.; Srinivasan, J.;
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Novel Tri- and Tetra-Cyclic Perhydroquinoline Architectures via an
Intramolecular [3 + 2] Cycloaddition Reaction. Org. Biomol. Chem.
2015, 13, 2870−2874. (d) Ghandi, M.; Kia, M. A.; Sadeghzadegh, M.;
Bozcheloei, A. H.; Kubicki, M. Diastereoselective Synthesis of Novel
Pyrrolidine or Pyrrolizine-Fused Benzo-δ-Sultams via 1,3-Dipolar
Cycloadditions. J. Heterocycl. Chem. 2015, 52, 1646−1653. (e) Sarrafi,
Y.; Sadatshahabi, M.; Hamzehloueian, M.; Alimohammadi, K.;
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(26) For each of the W- or S-shaped ylides shown, the moderately
flexible tether is likely capable of adopting the necessary conformation
to deliver the pendant arene for cycloaddition, but the precise
orientation of approach (exo or endo) need not be considered here,
as subsequent elimination of HNO2 takes place to restore aromaticity
(see Scheme 2).
F
DOI: 10.1021/acs.orglett.9b01580
Org. Lett. XXXX, XXX, XXX−XXX