Improved radical approach to N-Unsubstituted indol-2-one and dihydro-2-quinolinone compounds bearing spirocyclic cyclohexanone/ cyclohexadienone rings

Article abstract of DOI:10.1002/adsc.201000067

N-Unsubstituted indol-2-one and 3,4-dihydro-2-quinolinone compounds bearing spirocyclic cyclohexanone/cyclohexadienone rings can be accessed through a novel, improved method entailing the key radical spirocyclization of easily accessible N-methoxymethyl (MOM)-protected 2-iodoanilides derived from 4-azidobenzoic and 2-(4-azidophenyl)acetic acid.

Full text of DOI:10.1002/adsc.201000067

FULL PAPERS
DOI: 10.1002/adsc.201000067
Improved Radical Approach to N-Unsubstituted Indol-2-one
and Dihydro-2-quinolinone Compounds Bearing Spirocyclic
Cyclohexanone/Cyclohexadienone Rings
Tommaso Lanza,a Matteo Minozzi,a Alessandro Monesi,a Daniele Nanni,a,*
Piero Spagnolo,a,* and Giuseppe Zanardia
a
Dipartimento di Chimica Organica “A. Mangini”, Universitꢀ di Bologna, Viale Risorgimento 4, 40136 Bologna, Italy
Fax : (+39)-051-209-3654; e-mail: nanni@ms.fci.unibo.it or spagnolo@ms.fci.unibo.it
Received: January 27, 2010; Revised: July 20, 2010; Published online: August 27, 2010
This paper is heartily dedicated to Professor Pier Carlo Montevecchi on the occasion of his retirement.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000067.
Abstract: N-Unsubstituted indol-2-one and 3,4-dihy- rived from 4-azidobenzoic and 2-(4-azidophenyl)ace-
dro-2-quinolinone compounds bearing spirocyclic cy- tic acid.
clohexanone/cyclohexadienone rings can be accessed
through a novel, improved method entailing the key
radical spirocyclization of easily accessible N-me- Keywords: azides; cyclization; radical reactions; si-
thoxymethyl (MOM)-protected 2-iodoanilides de- lanes; spiro compounds
Introduction
vasopressin inhibitor SR121463A 2,[1] whereas the N-
Boc dihydroquinolinones 3, in the presence of pri-
Spiroindolone 1 and spirodihydroquinolinones 3 are mary amines, act as effective progenitors of particular
pivotal intermediates in the synthesis of important tetracyclic ketones that are highly promising inter-
biologically active compounds. Indolone 1 is a key in- mediates for the synthesis of indole alkaloids display-
termediate in the preparation of the potent, selective ing a wide range of biological activities (Figure 1).[2,3]
Figure 1. Spiroketone derivatives as key intermediates in the syntheses of important biologically active compounds.
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As far as the dihydroquinolinones 3 are concerned,
these are achieved by standard reaction of the respec-
tive N-unsubstituted quinolinones 22 (see Scheme 5)
with Boc2O. However, the preparation of these quino-
lones 22 is to date restricted to a multistep protocol
entailing primary Heck cyclization of oxo-protected
2-(4-oxo-1-cyclohexenyl)-ortho-iodoacetanilides to di-
hydroquinolinones under harsh conditions,[2] followed
by deprotection, further protection of the amide func-
tion with Boc2O, and eventual oxidation of the cyclo-
hexenone moiety with an excess of selenium diox-
AHCTUNGTRENNUNG
azides[8b] we have discovered that easily accessible N-
methyl-substituted p-azidobenzanilides 7, as well as
the corresponding 2-(p-azidophenyl)acetanilides 8,
undergo smooth radical reaction with TTMSS/Et3B at
ambient temperature giving rise to precipitation of
extensive amounts of indolone/quinolinone imine hy-
droiodides 9/10, isolable by direct filtration of the re-
action mixtures (Scheme 2). Under these circumstan-
Scheme 1. Curran synthesis of spiroindolone 1 (Tr=CPh3).
Structures such as compound 1 have been synthe- ces, 5- or 6-membered spirocyclizations of the derived
sized starting from 4-oxo-protected cyclohexyl deriva- aryl radicals onto the respective azido-substituted aro-
tives,[4] oxindoles,[5] or substituted indolones.[6] More matic rings result in the highly efficient production of
recently, compound
1 was prepared by Curran transient cyclohexadieniminyl radicals, from which hy-
through reduction and deprotection of the indole spi- droiodide salts 9 and 10 eventually arise.[8] In such
rocyclohexadienone 6 arising from the radical spiro- cases, as expected, the presence of the N-alkyl sub-
cyclization of the p-trityloxy-substituted iodobenzani- stituent encourages the occurrence of amide rotamers
lide 5 mediated by tris(trimethylsilyl)silane (TTMSS) prone to spirocyclization. Indeed, homolytic spirocy-
and Et3B as initiator (Scheme 1).[7]
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
struction of the requisite trityloxy precursor 5 is not gen.[9]
trivial: this approach would be therefore more useful
The isolated imine compounds 9 and 10 undergo
if the starting materials were easier to prepare. mild hydrolytical conversion into the corresponding
Indeed, the synthesis of 5 entails deprotection and tri- dienones 11 and 12, thus allowing a straightforward
tylation of preliminary tert-butyldimethylsilyloxy access to N-methylindol-2-ones and N-methyl-3,4-di-
(TBSO)-substituted anilide 4, which, in turn, requires hydro-2-quinolinones bearing spirocyclohexadienone
preparation of TBS-protected 4-hydroxybenzoyl chlo- rings (Scheme 2).[8b]
ride (Scheme 1).
Scheme 2. Approach to spiranic indol-2-ones and 3,4-dihydro-2-quinolinones through spirocyclization of aryl radicals onto
aromatic azides.
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Improved Radical Approach to N-Unsubstituted Indol-2-one and Dihydro-2-quinolinone Compounds
Results and Discussion
tance of iodide 15 to form the usual aryl radicals with
TTMSS/Et3B remain obscure at this stage. It is hoped
In light of these successful findings, we envisioned that future studies will shed light on this very intrigu-
that a similar method could enable a rewarding syn- ing point.
thetic entry to N-Boc-substituted spirocyclic ana-
After ascertaining that the N-Boc anilides 13 and
logues, such as the spirooxindole 6 and spirodihydro- 15 were of no utility for the desired production of the
quinolinones 3, and/or their ultimate deprotected corresponding spirocyclohexadienones, we decided to
counterparts. Therefore, we were initially prompted examine the alternative use of N-MOM-substituted
to prepare the N-Boc-protected azidobenzamide 13 precursors. MOM (methoxymethyl) was envisioned as
and azidoacetamide 15 (Scheme 3) in order to prove an especially promising protecting group owing to its
their potential utility in the construction of indolone 6 fairly close affinity with the original N-methyl sub-
and dihydroquinolinone 3 (R=H), respectively. Fol- stituent as well as predictably fair removal under acid
lowing a procedure analogous to that previously em- conditions.
ployed for the preparation of anilides 7 and 8,[8b] the
N-Boc congeners 13 and 15 were readily obtained (Scheme 4) and the corresponding (azidophenyl)-acet-
through coupling of the appropriate N-Boc-2-iodoani- anilides 20a–c (Scheme 5) were hence easily synthe-
line with p-azidobenzoyl or 2-(p-azidophenyl)acetyl sized by coupling of the suitable 2-iodoaniline with
chloride.[10]
the respective azidoacyl chloride, followed by treat-
The N-MOM-substituted azidobenzanilide 16
AHCTUNGTRENNUNG
Under experimental conditions strictly comparable ment of the lithium salt of the ensuing benzamide or
with those adopted with compounds 7/8,[8b] the new acetamide with chloromethyl methyl ether.
azidobenzamide 13 was actually able to undergo radi-
The usual radical reaction of 16 with TTMSS/Et3B
cal spirocyclization in benzene solution in the pres- gave rise to precipitation of a large amount of imine
ence of TTMSS (1.2 equiv.) and Et3B (1.2 equiv.) af- hydroiodide 17, which was simply recovered by filtra-
fording the indolone imine hydroiodide 14 in good tion of the reaction mixture and then subjected to hy-
isolated yield (Scheme 3). However, subsequent ef- drolysis without any further purification: brief treat-
forts to achieve the protected (or deprotected) cyclo- ment in THF/water at 708C in the presence of some
hexadienone 6 upon conventional acid hydrolysis of hydrochloric acid led to isolation of the N-MOM-sub-
14[8b,11] unfortunately failed, probably owing to a high stituted spiroindolone 18 in 68% overall yield
propensity of 14 and/or 6 to suffer ring-cleavage of (Scheme 4). We were very pleased to discover that in-
the pyrrolinone moiety upon nucleophilic attack at dolinone 18 was even superior to the Boc-substituted
the lactam carbonyl carbon.[6] Total failure to achieve analogue 6 as precursor of spirocyclohexanone 1.
6 was also encountered even when the hydrolysis was Indeed, Pd-mediated hydrogenation of 18 afforded
attempted by slow passage of 14 down a neutral alu- the reduced cyclohexanone 19 in 93% yield; heating
mina column (Brockmann activity II).[12]
of 19 at 1008C in ethanol/water containing catalytic
Our aim at exploiting the iodoazidoacetanilide 15 amounts of hydrochloric acid and treatment of the en-
as synthetic precursor of dihydroquinolinone 3 (R= suing N-ethoxymethyl derivative with TFA gave the
H) was still more frustrated by the surprising finding final compound 1 in 75% yield.[13] Spiroindolone 1
that 15 remained virtually unchanged in the presence could hence be attained from 18 in an overall yield
of up to a three-fold excess of TTMSS and/or Et3B superior to that originally obtained from 6 (Scheme 4
(Scheme 3). The actual reasons for the striking reluc- and Scheme 1).
Scheme 3. Attempted spirocyclization reactions of azidobenzamide 13 and azidoacetamide 15.
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dard reaction of 20a–c with TTMSS/Et3B similarly led
to extensive precipitation of quinolone imine hydroio-
dides 21a–c, which were again separated by simple fil-
tration. Upon suitably prolonged heating at 808C in
ethanol/water in the presence of hydrochloric acid,
crude iminium salts 21a–c underwent expected hy-
drolysis along with concomitant removal of the MOM
substituent, hence allowing the direct isolation of the
deprotected dienones 22a–c in 55–62% yields based
on the starting azides 20a–c (Scheme 5).[14]
We have therefore discovered a very useful, novel
synthetic route to N-unsubstituted spirodihydroquino-
linones 22. Although the outcoming yields are a little
lower, compared to those previously reported, our
new approach to compounds 22 seems superior to the
one involving Heck cyclization of oxo-protected cy-
clohexenone anilides.[2b] In particular, it is remarkably
easier and quicker, entails far milder reaction condi-
tions, and, furthermore, avoids unattractive use of
precursors that require troublesome preparation of
protected 2-(4-oxo-1-cyclohexenyl)acetic acid.[15]
Conclusions
Scheme 4. Improved synthesis of spiroindolone 1 through
key radical cyclization of azidobenzamide 16.
We have shown that the radical spirocyclization of
easily accessible N-MOM-protected 2-iodoanilides de-
rived from 2-(4-azidophenyl)acetic acid allows an im-
proved approach to N-unsubstituted 3,4-dihydro-2-
quinolinones bearing spirocyclohexadienone rings,
compounds that have been very recently reported as
pivotal precursors of biologically important indole al-
kaloids. Application of an analogous radical method-
ology to a suitable N-MOM-substituted 4-azidobenza-
nilide enables an advantageous synthetic entry to the
oxindole spirocyclohexanone 1, a key intermediate in-
volved in the synthesis of the vasopressin inhibitor
SR121463A.
With respect to the previously reported methods,
these novel radical processes entail more easily acces-
sible precursors, avoid the use of troublesome proce-
dures and/or toxic reagents, and are characterized by
a superior atom economy quality. These features, ad-
ditionally associated with ease of work-up in the key
step (the imine hydroiodides can be effectively recov-
ered in high purity by straightforward filtration of the
reaction mixtures) may let these reactions enter the
Scheme 5. Improved synthesis of spirodihydroquinolinones
22 through key radical cyclization of azidoacetamides 20.
As a result, the spirocyclic compound 1 became realm of sustainable chemistry, a domain that is par-
available through a novel protocol, based on latest ticularly worthy when applied to the synthesis of bio-
radical chemistry of aromatic azides, which, besides logically significant targets.
providing a strongly enhanced yield of 1, employs a
more convenient azido precursor and also results in
highly minimized atom waste. Furthermore, this pro-
tocol compares favourably even with other reported
Experimental Section
non-radical methods.[1b,c,4–6]
Highly gratifying results were also obtained with
the azido substrates 20a–c. As a matter of fact, stan- new compounds are reported in the Supporting Information.
General experimental details and characterization data for
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Improved Radical Approach to N-Unsubstituted Indol-2-one and Dihydro-2-quinolinone Compounds
vent was then evaporated. The residual aqueous solution
General Procedure for the Preparation of
Azidoamides
was extracted several times with Et2O and the organic phase
was dried (MgSO4), filtered, and concentrated under
vacuum. The corresponding N-MOM-protected ketone was
obtained in 68–98% yield. This procedure was applied to
salts 17 and 21a–c to obtain spirocycle 18 and the N-MOM-
protected derivatives of 22a–c, respectively.
Method 2: To a solution of the imine hydroiodide salt
(0.25 mmol) in EtOH (12.5 mL) and water (12.5 mL) were
added 50 drops of concentrated hydrochloric acid. The re-
sulting mixture was stirred at 808C for 24 h and the solvent
was then evaporated. The residual aqueous solution was ex-
tracted several times with Et2O and the organic phase was
dried (MgSO4), filtered, and concentrated under vacuum.
Column chromatography of the residue (silica gel, n-hexane/
diethyl ether gradient) gave the corresponding ketone in
55–62% yield. This procedure was applied to salts 21a–c to
obtain compounds 22a–c. It is worth noting that this hydrol-
ysis method, when applied to salt 17, gave a very complicat-
ed mixture without any trace of the desired N-MOM-depro-
tected derivative of 18.
To a stirred solution of 4-azidobenzoic acid or 2-(4-azido-
phenyl)acetic acid (6.10 mmol) and DMF (few drops) in an-
hydrous dichloromethane (DCM) (17 mL) at 08C thionyl
chloride (0.53 mL, 7.32 mmol) was slowly added. The reac-
tion mixture was stirred overnight at room temperature. The
resulting acyl chloride was obtained in apparent quantitative
yield (GC-MS analysis) and was used for the next step with-
out further purification. To a stirred solution of 2-iodoaryla-
mine (5.0 mmol) in anhydrous DCM (58 mL) at room tem-
perature were added pyridine (0.8 mL, 10.0 mmol), DMAP
(0.060 g, 0.50 mmol), and the DCM solution of the previous-
ly prepared acyl chloride. The resulting mixture was stirred
overnight and then diluted with DCM (80 mL) and saturat-
ed aqueous NaHCO3 solution (40 mL). The separated or-
ganic layer was dried (MgSO4), filtered, and concentrated
under vacuum. Column chromatography of the residue gave
the pure amides in 70–80% yield.
General Procedure for the Preparation of N-(MOM)-
Protected Azidobenzamide (16) and Azidoacetamides
(20a–c)
5’-Ethoxy-1’-MOM-spiro[cyclohexane-1,3’-(3’H)-
indole]-2’,4-(1’H)-dione (19)
To
a stirred solution of diisopropylamine (0.147 mL,
To a stirred solution of 18 (0.305 g, 1.02 mmol) in ethyl ace-
tate (18 mL) 10% Pd/C (536 mg, 0.51 mmol of Pd) was
added; the reaction vessel was purged with hydrogen and
then kept under stirring under a hydrogen atmosphere
(2 bar) for 2 h. The crude reaction mixture was filtered over
silica gel eluting with Et2O. The solvent was concentrated
under vacuum and pure ketone 19 was obtained as a white
solid without any need for further purification; yield: 93%.
1.05 mmol) in anhydrous THF (5 mL) at 08C under a nitro-
gen atmosphere n-BuLi (1.6M in hexane, 0.650 mL,
1.05 mmol) was added dropwise via syringe. The reaction
mixture was then stirred for 20 min at 08C and the resulting
LDA solution was added dropwise to a stirred solution of
azidoamide (1.00 mmol) in anhydrous THF (5 mL) at 08C
under a nitrogen atmosphere. The resulting mixture was
stirred for 2 h at room temperature and then MOM-Cl
(0.151 mL, 2.00 mmol) was slowly added. The final reaction
mixture was stirred overnight at room temperature,
quenched with water, and the solvent was evaporated. The
residual aqueous solution was extracted several times with
Et2O and the organic phase was dried (MgSO4), filtered,
and concentrated under vacuum. Column chromatography
of the residue (silica gel, n-hexane/diethyl ether gradient)
gave the corresponding azido-N-MOM-protected amide in
70–80% yield.
5’-Ethoxyspiro[cyclohexane-1,3’-(3’H)-indole]-2’,4-
(1’H)-dione (1)
To a stirred solution of 19 (0.152 g, 0.500 mmol) in EtOH
(25 mL) and water (5 mL) 75 drops of concentrated hydro-
chloric acid were added. The resulting mixture was stirred at
1008C overnight and the solvent was then evaporated. The
residual aqueous solution was extracted several times with
DCM and the organic phase was dried (MgSO4), filtered,
and concentrated under vacuum. The resulting N-ethoxy-
methyl derivative was obtained in almost quantitative yield
and was used for the next step without further purification.
To a stirred solution of the previously prepared N-ethoxy-
methyl derivative in DCM (3 mL) neat TFA (3.0 mL,
40.0 mmol) was added. The resulting mixture was stirred at
408C for 4 h and then at room temperature overnight. Final-
ly, it was diluted with DCM and saturated aqueous NaHCO3
solution; the organic phase was dried (MgSO4), filtered, and
concentrated under vacuum. Column chromatography of the
residue (silica gel, DCM/Et2O gradient) gave pure amide 1;
yield: 75%.
General Procedure for Radical Cyclization Reactions
of Azides (16, 20a–c) and Hydrolysis of Imine
Hydroiodide Salts (17, 21a–c)[16]
To a stirred solution of the azide (0.5 mmol) in benzene or
toluene (8 mL) were successively added Et3B (620 mL,
1.2 equiv.) and TTMSS (190 mL, 1.2 equiv.). The resulting
mixture was stirred at room temperature under air until
total consumption of the starting material (usually over-
night). Filtration of the reaction mixture afforded the imine
hydroiodide salt, which was used for the next step without
further purification. For sake of thoroughness, compound
21a (64% yield) was however isolated and fully character-
ized. Two different methods were developed for hydrolysis
of the iminium salts.
Acknowledgements
Method 1: To a solution of the imine hydroiodide salt
(0.25 mmol) in THF or methanol (12 mL) and water (6 mL)
were added 20 drops of concentrated hydrochloric acid. The
resulting mixture was stirred at 808C for 1.5–4 h and the sol-
We gratefully acknowledge financial support from the Uni-
versity of Bologna (2008 Funds for Selected Research
Topics) and MIUR (2008 PRIN funds for “Properties and re-
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activity of free radicals in complex environments and their
role in oxidative processes and in organic synthesis”).
[9] a) J. Robertson, M. J. Palframan, S. A. Shea, K. Teha-
banenko, W. P. Unsworth, C. Winters, Tetrahedron
2008, 64, 11896; b) G. Bencivenni, T. Lanza, R. Leardi-
ni, M. Minozzi, D. Nanni, P. Spagnolo, G. Zanardi J.
Org. Chem. 2008, 73, 4721; c) D. H. Hey, G. H. Jones,
M. J. Perkins, J. Chem. Soc. C 1971, 116; see also ref.[7]
and d) D. H. Hey, C. W. Rees, A. R. Todd, J. Chem.
Soc. C 1967, 1518, where the authors reported an ex-
ample of synthesis of spirocyclic dienone derivatives by
trapping of 4-unsubstituted spirocyclohexadienyl radi-
cals by dioxygen.
[10] p-Azidobenzoyl and 2-(p-azidophenyl)acetyl chloride
are prepared by conversion of the commercially avail-
able amino acids into azides via conventional treatment
of the diazonium salts with sodium azide.
[11] Heating of the iminium hydroiodide 14 in methanol/
water or THF/water in the presence of hydrochloric
acid gave rise to unclear product mixtures from which
we gained no diagnostic 1H NMR data in favour of pro-
tected (or deprotected) indolone 6.
[12] I. G. C. Coutts, N. J. Culbert, M. Edwards, J. A. Had-
field, D. R. Musto, V. H. Pavlidis, D. J. Richards, J.
Chem. Soc. Perkin Trans. 1 1985, 1829.
[13] We happened to observe that deprotection of the oxin-
dole cyclohexanone 19 could be significantly improved
through a preliminary conversion of the methoxymethyl
to the ethoxymethyl group.
[14] Parallel experiments suggested that the imine hydroio-
dides 21, when similarly reacted in THF/water or meth-
anol/water, undergo usual hydrolysis exclusive of de-
protection of the MOM group (see Supporting Infor-
mation).
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