Radical cyclization approach to spirocyclohexadienones

Article abstract of DOI:10.1021/ol0477226

(Chemical Equation Presented) Cyclization of an aryl radical at the ipso position of a p-O-aryl-substituted acetamide or benzamide generates oxindoles or quinolones bearing spirocyclohexadienone rings. This versatile reaction is applied to formal synthese

Full text of DOI:10.1021/ol0477226

ORGANIC
LETTERS
2005
Vol. 7, No. 1
151-154
Radical Cyclization Approach to
Spirocyclohexadienones†
Felix Gonza´lez-Lo´pez de Turiso and Dennis P. Curran*
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
curran@pitt.edu
Received November 6, 2004
ABSTRACT
Cyclization of an aryl radical at the ipso position of a p-O-aryl-substituted acetamide or benzamide generates oxindoles or quinolones bearing
spirocyclohexadienone rings. This versatile reaction is applied to formal syntheses of the vasopressin inhibitor SR121463A and aza-galanthamine.
Spirocyclohexadienones such as spirooxindole 1 and spirodi-
hydroquinolone 4 are pivotal intermediates in the preparation
of biologically active compounds (Figure 1). Reduction of
spirocyclohexadienone 1 provides spirocyclohexanone 2, a
key intermediate in the synthesis of the potent and selective
vasopressin inhibitor SR121463A 3.1 Spirodihydroquinolone
4 is a key intermediate in the preparation of aza-galanthamine
5.2 Structures such as the spirooxindole 2 have been
synthesized starting from 4-oxo-protected cyclohexyl deriva-
tives,3 oxindoles,4 or substituted indolones.5 Reports on the
synthesis of spirodihydroquinolones such as 4 are less
abundant and involve the use of organometallic chemistry
to install the key quaternary center in a protected 4-oxo
cyclohexyl derivative.2
The formation of spirocyclohexadienones in radical cy-
clizations was first described by Hey in reactions of radicals
generated by photolysis of iodides or reduction of diazonium
salts,6 but the synthetic potential of this reaction has yet to
be recognized. We hypothesized that a radical cyclization
could be used to construct both the spirooxindole 1 and the
spirodihydroquinolone 4 starting from generalized cyclization
precursor 6 (Figure 2).
Aryl radical 7 derived from 6 can cyclize at the ortho
position (path a) to give 8a or the ipso position (path b) to
give 8b.7 These radicals might be in equilibrium through a
(4) (a) Venkatesan, H.; Davis, M. C.; Altas, Y.; Snyder, J. P.; Liotta, D.
C. J. Org. Chem. 2001, 66, 3653-3661. (b) Go¨nczi, C.; He´ja, G.; Csiko´s,
E.; Hermecz, I.; He´ja, G.; Illar, A.; Nagy, L.; Sa´nta-Csutor, A.; Simon, K.;
Smelko´-Esek, A.; Szomor, T. PTC Int. Appl. WO0105760, 2001; Chem.
Abstr. 2001, 134, 115851. (c) Foulon, L.; Garcia, G.; Serradeil-Le Gal, C.;
Valette, G. WO9715556 A1, 1997; Chem. Abstr. 1997, 127, 5010. (d)
Johnos, R. S.; Lovett, T. O.; Steven, T. S. J. Chem. Soc. C 1970, 796-
800.
† This paper is dedicated to Prof. Amos B. Smith, III, in honor of his
60th birthday.
(1) (a) Hala´sz, J.; Poda´nyi, B.; Sa´nta-Csutor, A.; Bo¨cskei, Z.; Simon,
K.; Hanusz, M.; Hermecz, I. J. Mol. Struct. 2003, 187-196. (b) Hermecz,
I.; Sa´nta-Csutor, A.; Go¨nczi, C.; He´ja, G.; Csiko´s, E.; Simon, K.; Smelko´-
Esek, A.; Poda´nyi, B. Pure Appl. Chem. 2001, 71, 1401-1409.
(2) Thal, C.; Guillou, C.; Beunard, J. C.; Gras, E.; Potier, P. E. U. Fr
2,826,005-A1; Chem. Abstr. 2003, 138, 39446.
(3) (a) Di Malta, A.; Foulon, L.; Garcia, G.; Nisato, D.; Roux, R.;
Serradeil-Le Gal, C.; Valette, G.; Wagon, J. US 5849780; Chem. Abstr.
1999, 130, 66390. (b) Jonsson, N. A.; Moses, P. SE 366309, 1974; Chem.
Abstr. 1985, 83, 479076. (c) Jonsson, N. A.; Moses, P. Acta Chem. Scand.
B 1974, 28, 225-232.
(5) Beccalli, E. M.; Clerici, F.; Gelmi, M. L. Tetrahedron 2003, 59,
4615-4622.
(6) (a) Horii, Z.; Uchida, S.; Nakashita, Y.; Tsuchida, E.; Iwata, C.; Iwata,
C. Chem. Pharm. Bull. 1974, 22, 583-586 and references therein. (b) Hey,
D. H.; Jones, G. H.; Perkins, M. J. J. Chem. Soc. C 1971, 116-122. (c)
Horii, Z.; Iwata, C.; Wakawa, S.; Nakashita, Y. Chem. Commun. 1970,
1039. (d) Hey, D. H.; Todd, A. R. J. Chem. Soc. C 1967 1518-1525.
(7) Studer, A. In Radicals in Organic Synthesis, 1st ed.; Renaud, P.,
Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 2, pp 44-60.
10.1021/ol0477226 CCC: $30.25
© 2005 American Chemical Society
Published on Web 12/15/2004

Figure 1. Examples and uses of key spirocyclohexadienone
intermediates.
Figure 2. Ortho and ipso cyclization pathways.
formal 1,2-shift.8 Oxidation9 of 8a gives 9 with the OR group
intact, while either oxidation or â-fragmentation10 of 8b
should give the target spirocyclohexadienone 10.
To test the viability of this approach, precursors 14a-d
and 15b were synthesized by coupling readily available
2-iodoanilines 11 and 12 and acyl chloride 13 (Scheme 1).11
Treatment of the TBS-protected phenols 14a and 15a with
TBAF gave alcohols 16 and 17. These were tritylated,
benzoylated, or methylated to give precursors 14b-d and
15b.
1). These were isolated by flash chromatography in 13 and
57% yields, respectively.
Interestingly, we found that the ratios of spirocyclic to
phenanthridinone products were different depending on the
group attached to the phenol. With the trityl or benzoyl
precursors 14b,c and 15b, the desired spirocyclic compounds
18 and 19 were the main products (entries 2, 3, and 5, Table
1), and purification by column chromatography allowed
isolation of the spirocyclic compounds in yields ranging from
With these precursors in hand, the key cyclization reactions
were tested employing the (Me3Si)3SiH/Et3B method.12 In a
typical experiment, a solution of 14a in benzene (0.15 M)
was treated with 1.2 equiv of (Me3Si)3SiH and 1.2 equiv of
Et3B, and the resulting mixture was stirred at room temper-
ature open to air until the starting material was consumed
(typically 3 h). Subsequent evaporation and 1H NMR
spectroscopic analysis showed spirocyclic compound 18 and
the phenanthridinone 20a as the only products (entry 1, Table
Scheme 1
(8) Studer, A.; Bossart, M. Tetrahedron 2001, 57, 9649-9667.
(9) Beckwith, A. L. J.; Bowry, V. W.; Bowman, W. R.; Mann, E.; Parr,
J.; Storey, J. M. D. Angew. Chem., Int. Ed. 2004, 43, 95-98.
(10) Dreessen, T.; Jargstorff, C.; Lietzau, L.; Plath, C.; Stademann, A.;
Wille, U. Molecules 2004, 9, 480-497.
(11) See Supporting Information for experimental details on the prepara-
tion of these compounds.
(12) (a) Chatgilialoglu, C.; Ferreri, C.; Gimisis, T. In Chemistry of
Organic Silicon; Rappoport, Z., Apeloig, Y., Eds.; Wiley: Chichester, 1998;
Vol. 2, pp 1539-1579. (b) Yorimitsu, H.; Oshima, K. In Radicals in
Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim,
2001; Vol. 1, pp 11-27.
152
Org. Lett., Vol. 7, No. 1, 2005

Scheme 3. Synthesis of Cyclization Precursors
Table 1. Synthesis of Spirooxindoles 18/19 and
Phenanthridinones 20/21
precursor
R′′
R
product
ratioa
yieldb
14a
14b
14c
14d
15b
H
H
H
H
TBS
Tr
Bz
Me
Tr
18/20a
18/20b
18/20c
18/20d
19/21
1/4.4
2.2/1
1.5/1c
1/2.6
1/0
13%/57%
43%/ndd
29%/ndd
15%/38%
53%
Me
a Ratio determined by 1H NMR spectroscopy. b Isolated yield after
column chromatography. c Reaction did not go to completion. d Not deter-
mined (purification was not possible by column chromatography).
acyl chloride 13 gave the amide 24, which was deprotected
with TBAF to give alcohol 25. Treatment of this alcohol
with trityl chloride in the presence of Et3N and DMAP
provided the key cyclization precursor 26. Gratifyingly,
cyclization of 26 under the standard conditions (0.15 M in
benzene, (Me3Si)3SiH, Et3B, open to air) gave the desired
spirocyclic compound 1 in 34% yield. Subsequent Pd-
mediated hydrogenation of dienone 1 and removal of the
Boc group with TFA gave the desired spirocyclohexanone
2, an intermediate previously reported in the synthesis of
SR121463A.1b
Having established the viability of this approach in the
synthesis of spirooxindoles, we turned our attention to the
preparation of spirodihydroquinolones. The required cycliza-
tion precursors 30a, 31, and 32 were synthesized by the
coupling reaction of the readily available iodoanilines 11,
12, or 28 with acyl chloride 29 (Scheme 3).11 Subsequent
deprotection of the TBS group in 30a provided alcohol 33,
which was reacted with trityl chloride in the presence of
DMAP and Et3N to give precursor 30b.
29 to 53%. In contrast, when the cyclization was performed
with the TBS- or methyl-protected precursors 14a,d, the main
products were the phenanthridinones 20a,d, which were
isolated in yields ranging from 38 to 57% (entries 1 and 4,
Table 1). Importantly, these experiments revealed suitable
precursors for the selective formation of either the spirocyclic
(18, 19) or phenanthridinone (20a-d, 21) products, setting
the stage for the synthesis of the spirocyclic compound
SR121463A 3.
The approach to vasopressin inhibitor 3 started with the
readily available protected aniline 22 (Scheme 2).11 Directed
Scheme 2. Formal Synthesis of SR121463A
The key cyclization reactions were performed under the
previous reaction conditions with precursors 30a,b, 31, and
32. Evaporation of the crude reaction mixture after the
starting material was consumed (typically 2 h) and purifica-
tion by column chromatography provided the desired spirodi-
hydroquinolones 34, 35, and 36 in yields shown in Table 2.
All the products resulted from the ipso cyclization, and there
was no evidence for products of ortho cyclization.
Interestingly, the target spirohydroquinolines 34-36 were
isolated in acceptable yields starting from the corresponding
TBS-protected precursors 30a, 31, and 32. The trends of
yields in these reactions were typically between 40 and 65%
depending on the substitution of the aromatic ring of the
cyclization precursors. These experiments allowed us to
identify suitable precursors for the synthesis of spirodihy-
droquinolones, prompting us to consider application of this
method to a formal synthesis of aza-galanthamine 5.
The approach toward aza-galanthamine 5 started with the
readily available trisubstituted aromatic ring 37,11 which was
ortho lithiation of 22, followed by treatment of the resulting
anion solution with 1,2-diiodoethane, gave iodoaniline 23
in 63% yield. Coupling of the protected aniline 23 and the
Org. Lett., Vol. 7, No. 1, 2005
153

Scheme 4. Formal Synthesis of aza-Galanthamine
Table 2. Synthesis of Spirodihydroquinolones
precursor
R′′
R
product
yielda
30a
30b
31
H
H
Me
Br
TBS
Tr
TBS
TBS
34
34
35
36
49%
65%
53%
40%
32
a Isolated yield after column chromatography.
synthesis of a number of spirocyclic compounds, including
key intermediates in the synthesis of both SR121463A and
aza-galanthamine. In some cases, the products of ortho
substitution (phenanthridinones) are also observed, and the
ratio of ortho- to ipso-substituted products can be controlled
by the oxygen substituent. Substituents favoring â-fragmen-
tation (trityl) give more ipso-substitution product, while
substituents disfavoring it (methyl) give more ortho-substitu-
tion product.
protected by deprotonation with LDA and treatment of the
resulting anion solution with methyl iodide. Boc deprotection
of 38 by using TFA, followed by condensation with the
corresponding acyl chloride 29, gave the desired cyclization
precursor 40 in 64% yield. Gratifyingly, we found that when
precursor 40 was treated under the radical cyclization
conditions, the desired spirodihydroquinolone 4 was isolated
in 40% yield (Scheme 4).13
In summary, we have introduced a new procedure for the
synthesis of spirooxindoles and spirodihydroquinolones
through ipso cyclization of aryl radicals to oxygen-substituted
aromatic rings. The reaction allows quick access to a variety
of spirocyclic structures starting from simple cyclization
precursors. The usefulness of the method is shown by the
Acknowledgment. We thank the National Science Foun-
dation for funding this work.
Supporting Information Available: Experimental pro-
1
cedures, characterization data, and H and 13C NMR data
for new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(13) Compound 4 showed 1H NMR data identical to that reported in the
literature (see ref 2). The published 13C NMR data lack the quaternary carbon
that resonates at δ ) 43.6 ppm.
OL0477226
154
Org. Lett., Vol. 7, No. 1, 2005