Oxidative rearrangement of Indoles: A new approach to the EFHG-tetracyclic core of diazonamide A

Article abstract of DOI:10.1021/jo062627r

(Chemical Equation Presented) A new approach to the ring EFHG-tetracyclic core fragment of the marine secondary metabolite diazonamide A is described. The route is based on the oxidative rearrangement of 3-arylindole-2-carboxylates. Thus, a range of 3-arylindole-2-carboxylates (3, 8) underwent rearrangement to the corresponding 3,3-disubstituted oxindoles (4, 9) with migration of the ester group upon treatment with tert-butyl hypochlorite followed by acid. The oxindoles 9 with a 3-[2-(4-methoxybenzyloxy)]phenyl substituent underwent cyclization to the tetracyclic aminals 11 following N-protection, reduction, and treatment with methanesulfonic anhydride. The methodology was applied to the tyrosine-indole derivative 17 to give the EFHG-tetracyclic core of diazonamide A.

Full text of DOI:10.1021/jo062627r

Oxidative Rearrangement of Indoles: A New Approach to the
EFHG-Tetracyclic Core of Diazonamide A
Cyril Poriel,† Mathilde Lachia,‡ Claire Wilson,‡ James R. Davies,† and
Christopher J. Moody*,‡
Department of Chemistry, UniVersity of Exeter, Stocker Road, Exeter EX4 4QD, United Kingdom, and
School of Chemistry, UniVersity of Nottingham, UniVersity Park, Nottingham NG7 2RD, United Kingdom
c.j.moody@nottingham.ac.uk
ReceiVed December 21, 2006
A new approach to the ring EFHG-tetracyclic core fragment of the marine secondary metabolite
diazonamide A is described. The route is based on the oxidative rearrangement of 3-arylindole-2-
carboxylates. Thus, a range of 3-arylindole-2-carboxylates (3, 8) underwent rearrangement to the
corresponding 3,3-disubstituted oxindoles (4, 9) with migration of the ester group upon treatment with
tert-butyl hypochlorite followed by acid. The oxindoles 9 with a 3-[2-(4-methoxybenzyloxy)]phenyl
substituent underwent cyclization to the tetracyclic aminals 11 following N-protection, reduction, and
treatment with methanesulfonic anhydride. The methodology was applied to the tyrosine-indole derivative
17 to give the EFHG-tetracyclic core of diazonamide A.
Introduction
However, in 2001 when Harran and co-workers completed a
total synthesis of structure 1, they discovered that it was different
The marine natural product diazonamide A, isolated from the
colonial ascidian (sea squirt) Diazona chinensis, was assigned
as structure 1 in 1991 on the basis of an X-ray crystallographic
study of a derivative.1 The combination of a unique and complex
structure, and the reported potent biological activity against
human tumor cell lines,1,2 ensured that diazonamide A im-
mediately captured the imagination of synthetic organic chem-
ists. Hence, in the 15 years since the structure of diazonamide
A was published, more than 10 research groups worldwide have
reported approaches to this interesting natural product.3-32
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42, 627.
* Corresponding author. Tel.: 44-115-846-8500. Fax: 44-115-951-3564.
† University of Exeter.
‡ University of Nottingham.
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10.1021/jo062627r CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/17/2007
2978
J. Org. Chem. 2007, 72, 2978-2987

OxidatiVe Rearrangement of Indoles
attraction as a target for organic synthesis that it continues to
hold the attention of a number of research groups. Of particular
interest is the tetracyclic core of the molecule, comprising rings
EFHG and the C-10 quaternary asymmetric center, and various
approaches have been reported. Much of the early work was
directed toward old diazonamide A and, for example, involved
arylation or alkylation of benzofuranones,3,24 DMAP catalyzed
rearrangement of 2-acyloxybenzofurans to 3-acylbenzofura-
nones,20,22 and intramolecular Heck reactions.5,40 Unsurprisingly,
some of these strategies have also been applied to the correct
structure, substituting the relevant oxindole for a benzofuranone.
Thus, arylation, alkylation, and acylation reactions of 3-substi-
tuted oxindoles have been employed,23,35-38 as have intramo-
lecular Heck reactions,8 oxindole rearrangements,41,42 rhodium
carbene chemistry,25 and intramolecular capture of a tyrosine-
derived phenoxenium ion by an indole.39
Our own interest in diazonamide A started over a decade ago
when we reported an approach to a benzofuranone related to
the original structure using the DMAP-induced C-acylation
reaction and an approach to 5-(3-indolyl)oxazoles using dirhod-
ium(II) catalyzed reactions of diazocarbonyl compounds.43,44
More recently, we have described further approaches to the
tyrosine-derived unit using the Claisen rearrangement or an
intramolecular Heck reaction45,46 and a range of studies on the
indole-oxazole fragments,47-49 including a biomimetic route
based on the oxidation of a Try-Val-Trp-Trp tetrapeptide.50 We
now report a new approach to the tetracyclic ring EFHG core
of diazonamide A using the oxidative rearrangement of indoles
as the key step.
FIGURE 1. Original and revised structures for the marine secondary
metabolite diazonamide A.
from the natural product.33,34 After a re-examination of the
original X-ray data, Harran proposed structure 2 for diazonamide
A (Figure 1). Not only did this subsequently prove to be correct,
but it also better fits a biosynthetic route in which the bicyclic
core could be derived from modification of a Tyr-Val-Trp-
Trp tetrapeptide. Final proof that the revised structure 2 was
indeed that of diazonamide A came in 2002 when Nicolaou
and co-workers published the first total synthesis of the natural
product.35,36 Subsequently, the Nicolaou group reported a second
route to diazonamide A,37,38 while Harran and co-workers
completed their own total synthesis of the correct structure.39
Although Nicolaou’s and Harran’s endeavors have now
solved the structural problem of diazonamide A, such is its
Results and Discussion
Our retrosynthetic analysis of diazonamide A 2 is based on
the disconnection of one biaryl and two amide bonds, which
together with formation of the ring A oxazole, leads directly
back to the EFHG-tetracyclic core, that by analogy with the
aforementioned published work, should be available from the
3,3-disubstituted oxindole shown in Scheme 1. The choice of a
p-methoxybenzyl (PMB) protecting group for the phenolic
oxygen is influenced by the work of Vedejs and Zajac who
demonstrated its facile removal under conditions required to
cyclize the H-ring.23 The key to the whole strategy is therefore
the synthesis of a suitable 3,3-disubstituted oxindole precursor,
and hence, we sought to investigate the oxidative rearrangement
of indoles as a potential route.
(25) Sawada, T.; Fuerst, D. E.; Wood, J. L. Tetrahedron Lett. 2003, 44,
4919.
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Angew. Chem., Int. Ed. 2000, 39, 3473.
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M.; Reddy, M. V.; Snyder, S. A. Angew. Chem., Int. Ed. 2001, 40, 4705.
(28) Nicolaou, K. C.; Snyder, S. A.; Huang, X. H.; Simonsen, K. B.;
Koumbis, A. E.; Bigot, A. J. Am. Chem. Soc. 2004, 126, 10162.
(29) Nicolaou, K. C.; Snyder, S. A.; Giuseppone, N.; Huang, X. H.; Bella,
M.; Reddy, M. V.; Rao, P. B.; Koumbis, A. E.; Giannakakou, P.; O’Brate,
A. J. Am. Chem. Soc. 2004, 126, 10174.
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(31) Schley, D.; Radspieler, A.; Christoph, G.; Liebscher, J. Eur. J. Org.
Chem. 2002, 369.
The oxidative rearrangement of indoles to oxindoles upon
treatment with electrophilic halogenating agents has been known
for several decades. Although the reaction has been investigated
(32) Feldman, K. S.; Eastman, K. J.; Lessene, G. Org. Lett. 2002, 4,
3525.
(33) Li, J.; Jeong, S.; Esser, L.; Harran, P. G. Angew. Chem., Int. Ed.
2001, 40, 4765.
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Angew. Chem., Int. Ed. 2001, 40, 4770.
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T.; Snyder, S. A. Angew. Chem., Int. Ed. 2002, 41, 3495.
(36) Nicolaou, K. C.; Chen, D. Y. K.; Huang, X. H.; Ling, T. T.; Bella,
M.; Snyder, S. A. J. Am. Chem. Soc. 2004, 126, 12888.
(37) Nicolaou, K. C.; Rao, P. B.; Hao, J. L.; Reddy, M. V.; Rassias, G.;
Huang, X. H.; Chen, D. Y. K.; Snyder, S. A. Angew. Chem., Int. Ed. 2003,
42, 1753.
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Snyder, S. A.; Huang, X. H.; Chen, D. Y. K.; Brenzovich, W. E.;
Giuseppone, N.; Giannakakou, P.; O’Brate, A. J. Am. Chem. Soc. 2004,
126, 12897.
(40) Bringmann, G.; Tasler, S.; Endress, H.; Peters, K.; Peters, E. M.
Synthesis 1998, 1501.
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Appl. Chem. 1994, 66, 2107.
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Soc., Perkin Trans. 1 1997, 2413.
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Slawin, A. M. Z.; Moody, C. J. Org. Biomol. Chem. 2005, 3, 3805.
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41, 6897.
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41, 6901.
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7305.
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J. Org. Chem, Vol. 72, No. 8, 2007 2979

Poriel et al.
SCHEME 1. Retrosynthetic Analysis of Diazonamide Aa
SCHEME 2
oxindole 4c was confirmed by X-ray crystallography (see
Supporting Information);62 attempted reduction using diisobu-
tylaluminum hydride, however, did not result in the formation
of the desired oxindole 4b.
a Pg ) protecting group.
To incorporate the essential functionality for formation of
the ring EFHG-tetracycle, we next investigated 3-arylindole-
2-carboxylate 8a, prepared from ethyl indole-2-carboxylate 5a,
by iodination (93%) and palladium catalyzed cross coupling of
the iodide 6a with the PMB protected phenolic boronate ester
7, available from 2-iodophenol by alkylation and boration. The
boration using the standard Miyaura conditions63 was low
yielding, probably due to the steric hindrance of the aryl iodide.
Baudoin reported a modification of Masuda’s method for the
conversion of ortho-substituted aryl bromides and iodides using
Pd(OAc)2, 2-(dicyclohexylphosphino)biphenyl as a ligand, and
pinacolborane as a boron source.64,65 Under these conditions,
the alkylated 2-iodophenol was efficiently converted into the
corresponding boronate ester 7 as shown in Scheme 3. Upon
treatment with tert-butyl hypochlorite followed by HCl in
ethanol, the indole 8a underwent oxidative rearrangement to
the 3,3-disubstituted oxindole 9a in excellent yield. Some care
was necessary to avoid cleavage of the PMB protecting group
under the acidic conditions. The reaction sequence was repeated
starting from ethyl 7-bromoindole-2-carboxylate 5b, prepared
from 2-bromophenylhydrazine and ethyl pyruvate in a Fischer
indole reaction. As expected, selective cross coupling with the
iodide was possible, although the yield of the indole 8b was
modest, and the use of the PdCl2(dppf) catalyst at 35 °C was
essential to avoid over-reaction at the C-7 bromide. Oxidative
rearrangement as before gave the oxindole 9b (Scheme 3).
With a suitably substituted oxindole available, attention was
turned to its conversion into the diazonamide tetracyclic core
ring system. Therefore, the nitrogen in oxindole 9 was protected
with either tert-butyl or allyl carbamate 10 (Scheme 4), the
structure of the Boc-derivative 10a being confirmed by X-ray
crystallography (see Supporting Information).62
in simple indoles,51-54 and its mechanism studied in detail,55,56
it has also found use in indole alkaloids57,58 and has recently
been elegantly exploited in a biogenetically patterned transfor-
mation of the Corynanthe skeleton into the Strychnos system.59
Our own work started with an extension of the seminal work
by Walser et al.54 Thus, ethyl 7-bromo-3-phenylindole-2-
carboxylate 3a, prepared from 2-bromoaniline and ethyl 2-ben-
zyl-3-oxobutanoate in a Japp-Klingemann synthesis,60 was
treated with tert-butyl hypochlorite followed by ethanolic HCl
to give, after chromatography, the 3,3-disubstituted oxindole
4a in excellent yield (Scheme 2). The generally accepted
mechanism involves conversion of the indole into a 3-haloin-
dolenine, followed by protonation and attack of a nucleophile
(water) and finally migration of the ester group, concomitant
with loss of chloride, to form the oxindole. In an attempt to
introduce other functionality at the oxindole 3-position, the
corresponding aldehyde 3b was investigated. Unfortunately, the
aldehyde 3b, prepared from the ester 3a by reduction with
lithium aluminum hydride followed by oxidation with manga-
nese(IV) oxide, did not undergo oxidative rearrangement to give
the desired oxindole 4b. It was previously noted by Walser et
al. that related 2-acetylindoles did not give the expected
3-acetyloxindoles upon oxidative rearrangement.54 On the hand,
the Weinreb amide 3c, prepared by reaction of ester 3a with
N,O-dimethylhydroxylamine in the presence of dimethylalumi-
num chloride,61 underwent smooth oxidative rearrangement to
give the oxindole 4c (85%) (Scheme 2). The structure of
(51) Acheson, R. M.; Vernon, J. M.; Snaith, R. W. J. Chem. Soc. 1964,
3229.
(52) Acheson, R. M.; Prince, R. J.; Procter, G. J. Chem. Soc., Perkin
Trans. 1 1979, 595.
(53) Muchowski, J. M. Can. J. Chem. 1970, 48, 422.
(54) Walser, A.; Blount, J. F.; Fryer, R. I. J. Org. Chem. 1973, 38, 3077.
(55) De Rosa, M.; Alonso, J. L. T. J. Org. Chem. 1978, 43, 2639.
(56) De Rosa, M.; Carbognani, L.; Febres, A. J. Org. Chem. 1981, 46,
2054.
(57) Finch, N.; Taylor, W. I. J. Am. Chem. Soc. 1962, 84, 3871.
(58) Lichman, K. V. J. Chem. Soc. C 1971, 2539.
(59) Ito, M.; Clark, C. W.; Mortimore, M.; Goh, J. B.; Martin, S. F. J.
Am. Chem. Soc. 2001, 123, 8003.
(62) X-ray crystal data: these can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html or from the Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge, CB21EZ, UK; fax: 44-
1223-336-033 or e-mail: deposit@ccdc.cam.ac.uk.
(63) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60,
7508.
(64) Baudoin, O.; Guenard, D.; Gueritte, F. J. Org. Chem. 2000, 65,
9268.
(65) Murata, M.; Watanabe, S.; Masuda, Y. J. Org. Chem. 1997, 62,
6458.
(60) Sundberg, R. J. The Chemistry of Indoles; Academic Press: New
York, 1970.
(61) Shimizu, T.; Osako, K.; Nakata, T. Tetrahedron Lett. 1997, 38, 2685.
2980 J. Org. Chem., Vol. 72, No. 8, 2007

OxidatiVe Rearrangement of Indoles
SCHEME 3
SCHEME 5
SCHEME 4
leads to decarboxylation and isolation of the indole 13 (X )
H, R ) t-Bu) in good yield. Finally, in this series of model
compounds, the Boc protecting group was removed from
tetracycle 11a to give the crystalline NH compound 14
(Scheme 4), X-ray crystallographic analysis of which (see
Supporting Information)62 confirmed the cis-stereochemistry of
the 5,5-system.
Having established methodology for the formation of 3,3-
disubstituted oxindoles and their subsequent conversion into
tetracyclic compounds, we embarked on the synthesis of the
complete tetracyclic aminal core of diazonamide incorporating
the correct tyrosine side chain. The starting material was the
protected iodotyrosine 15, previously prepared in our earlier
studies on diazonamide.46 Protection of the phenol as its PMB
ether was followed by a palladium catalyzed reaction with
pinacolborane to give the tyrosine boronate 16 (Scheme 5). A
second palladium catalyzed reaction under Suzuki conditions
then combined the indole 6b and tyrosine 16 fragments to give
the 3-arylindole-2-carboxylate 17. The key oxidative rearrange-
ment then proceeded as planned to provide the oxindole 18 in
an acceptable yield of 68%, albeit as an inseparable mixture of
diastereoisomers. Finally, protection of the oxindole NH as its
allyl carbamate, followed by application of the Vedejs protocol,
delivered the tetracyclic aminal core 19 of diazonamide A, again
as an inseparable mixture of diastereoisomers (Scheme 5). The
diastereoisomers of tetracycle 19 both have a cis-fused 5-5
system but are diastereomeric with respect to the tyrosine-
derived stereocenter.
Thereafter, using the methodology established by Vedejs and
Zajac,22 sodium borohydride reduction of the oxindole carbonyl
followed by treatment with methanesulfonic anhydride resulted
in cyclization to the tetracyclic aminal 11 with concomitant
removal of the PMB protecting group in good yield for all three
substrates 10 (Scheme 4). The 5,5-system 11 was isolated as a
single diastereoisomer. Initial attempts to hydrolyze the ester
in compound 11 were unsuccessful and invariably led to loss
of the ester, presumably by decarboxylation of the acid 12, and
formation of the indole 13 by an aromatization reaction with
the phenolate acting as a good leaving group. However, under
milder hydrolysis conditions, the acids 12a and 12b could be
isolated in good yield. Heating the acid 12a to about 95 °C
Hence, we have shown that the long known oxidative
rearrangement of indoles to oxindoles upon treatment with an
electrophilic chlorinating reagent can be used to access 3,3-
disubstituted oxindoles appropriately substituted for conversion
into the EFHG-tetracyclic aminal core of diazonamide A. In
J. Org. Chem, Vol. 72, No. 8, 2007 2981

Poriel et al.
parallel work,66 we have recently shown that use of a 2-meth-
oxymethylpyrrolidine chiral auxiliary in place of the ethyl ester
results in a diastereoselective rearrangement to give, after
crystallization, optically pure oxindoles. This methodology,
combined with that described herein, is under investigation as
a route to diazonamide A.
acetate (2 × 50 mL), and the combined organic layers were washed
with brine, dried (Na2SO4), filtered, and concentrated. The residue
was recrystallized from light petroleum/acetate to afford 2-(4-
methoxybenzyloxy)iodobenzene as a colorless solid (3.15 g, 99%);
mp 101-102 °C; IR (KBr/cm-1) 3008, 2955, 2932, 2833, 1610,
1580, 1567, 1515, 1478, 1465, 1438, 1375, 1303, 1281, 1241, 1178,
1164, 1115, 1052, 1030, 1016, 992, 868, 754; 1H NMR (270 MHz;
CDCl3) δ 7.80 (1 H, dd, J 7.8, 1.5), 7.43 (2 H, d, J 8.7), 7.28 (1 H,
ddd, J 8.2, 7.4, 1.5), 6.94 (2 H, d, J 8.7), 6.88 (1 H, dd, J 1.2, 8.2),
6.73 (1 H, ddd, J 7.6, 7.4, 1.2), 5.09 (2 H, s), 3.83 (3 H, s); 13C
NMR (75 MHz; CDCl3) δ 159.7 (C), 157.7 (C), 139.9 (CH), 129.9
(CH), 129.2 (CH), 129 (C), 123.3 (CH), 114.4 (CH), 113.3 (CH),
87.4 (C), 71.1 (CH2), 55.7 (Me), MS (CI) 341 (MH+, 16%), 232
(39), 213 (14), 121 (100); Found: MH+, 341.0038. C14H13IO2 +
H requires: 341.0033. Found: C, 49.27; H, 3.82. C14H13IO2
requires: C, 49.43; H, 3.85%.
Experimental Section
For general experimental details and the preparation of starting
indoles 3a, 3b, 3c, 5b, 6a, and 6b, see the Supporting Information.
Ethyl 7-Bromo-2-oxo-3-phenylindole-3-carboxylate 4a. To a
solution of tert-butyl hypochlorite (400 mg, 3.6 mmol) in dichlo-
romethane (3 mL) was added ethyl 7-bromo-3-phenylindole-2-
carboxylate 3a (400 mg, 1.2 mmol) in dichloromethane (3 mL),
and the mixture was stirred for 30 min at room temperature. The
reaction mixture was concentrated under reduced pressure, and the
residue was dissolved in a mixture of dichloromethane (9.5 mL),
ethanol (6.5 mL), and a solution of HCl in ethanol (5%, 1.5 mL)
and stirred overnight. The reaction mixture was concentrated under
reduced pressure, and the residue was purified by flash chroma-
tography to yield the title product as a colorless crystalline solid
(406 mg, 97%); mp 95 - 97 °C; IR (KBr/cm-1) 3237, 3088, 3001,
(b) Triethylamine (2.76 mL, 10 mmol) was added to a degassed
solution of 2-(4-methoxybenzyloxy)iodobenzene (1.70 g, 5 mmol),
palladium acetate (11 mg, 0.05 mmol), and 2-(dicyclohexylphos-
phino)biphenyl (70 mg, 0.20 mmol) in anhydrous dioxane (23 mL)
under argon. The resulting solution was degassed again before the
slow addition of pinacolborane (2.24 mL, 15 mmol). The resulting
dark-green solution was heated to 85 °C for 10 min and was then
cooled to 0 °C. Saturated aqueous ammonium chloride (30 mL)
was added carefully, and the reaction mixture was extracted with
ether (3 × 25 mL). The combined organic layers were dried
(Na2SO4), filtered, and concentrated. The residue was purified by
flash chromatography eluting with light petroleum/ethyl acetate (17:
3) and recrystallized from light petroleum. The title compound was
obtained as a colorless solid (1.36 g, 82%); mp 79-81 °C; IR (KBr/
cm-1) 2976, 2935, 2885, 1613, 1600, 1575, 1516, 1490, 1448, 1354,
1
2981, 2925, 2853, 1737, 1721, 1614, 1470, 1450, 1224; H NMR
(300 MHz; CDCl3) δ 7.94 (1 H, s), 7.49-7.46 (1 H, m), 7.39-
7.30 (6 H, m), 7.03 (1 H, t, J 7.9), 4.34-4.16 (2 H, m), 1.22 (3 H,
t, J 7.1); 13C NMR (75 MHz; CDCl3) δ 173.3 (C), 168.8 (C), 141.3
(C), 135.6 (C), 132.7 (CH), 129.1 (CH), 128.9 (CH), 128.1 (CH),
125.6 (CH), 124.5 (CH), 103.6 (C), 66.0(C), 63.1 (CH2), 14.3 (Me);
MS (CI) 362/360 (MH+, 100/95%), 359 (5), 317 (4), 316 (8), 289
(8), 288 (30), 282 (48), 281 (5), 266 (1), 236 (4), 222 (2), 210 (5),
208 (10); Found: MH+, 360.0244. C17H1479BrNO3 + H requires:
360.0236. Found: C, 56.48; H, 3.77; N, 3.65. C17H14BrNO3
requires: C, 56.69; H, 3.92; N, 3.89%.
1
1271, 1249, 1141, 1073, 1049, 1035; 835, 826, 762; H NMR
(400 MHz; CDCl3) δ 7.69 (1 H, dd, J 7.2, 1.7), 7.51 (2 H, d, J
8.6), 7.39 (1 H, ddd, J 8.3, 7.4, 1.7), 6.96 (1 H, d, J 7.3), 6.94 -
6.89 (3 H, m), 5.05 (2 H, s), 3.82 (3 H, s), 1.36 (12 H, s); 13C
NMR (100 MHz; CDCl3) δ 163.3 (C), 158.9 (C), 136.6 (CH), 132.4
(CH), 129.8 (C), 128.3 (CH), 120.6 (CH), 113.5 (CH), 112.3 (CH),
83.4 (C), 69.9 (CH2), 55.3 (Me), 24.9 (Me); C-B carbon not
observed; Found: M+, 340.1837. C20H2511BO4 requires: 340.1846.
Found: C, 70.58; H, 7.63. C20H25BO4 requires: C, 70.40; H, 7.68%.
Ethyl 3-[2-(4-Methoxybenzyloxy)phenyl]indole-2-carboxylate
8a. To a degassed solution of ethyl 3-iodoindole-2-carboxylate 6a
(945 mg, 3 mmol) and 2-[2-(4-methoxybenzyloxy)phenyl]-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane 7 (1.22 g, 3.6 mmol) in DME
(28 mL) was added PdCl2(dppf)‚CH2Cl2 (122 mg, 0.15 mmol).
Then, potassium carbonate (1.65 g, 12 mmol) in water (4 mL) was
added slowly. The resulting red solution was stirred at 85 °C
overnight. The mixture was allowed to cool to room temperature,
water (50 mL) was added, and the solution was extracted with ethyl
acetate (3 × 100 mL). The combined organic layers were dried
(Na2SO4), filtered, and concentrated. The dark residue was purified
by flash chromatography eluting with light petroleum/ethyl acetate
(17:3) to give the title product as a colorless solid (974 mg, 81%);
mp 39-40 °C (from light petroleum); IR (neat/cm-1) 3320, 1676,
N-Methoxy-N-methyl 7-Bromo-2-oxo-3-phenylindole-3-car-
boxamide 4c. To a solution of N-methoxy-N-methyl 7-bromo-3-
phenyl-1H-indole-2-carboxamide (50 mg, 0.14 mmol) 3c in dichlo-
romethane (5 mL) was added tert-butyl hypochlorite (23 µL, 0.20
mmol), and the reaction mixture was stirred for 5 h protected from
the light. The reaction mixture was concentrated in vacuo, and the
residue was dissolved in a mixture of dichloromethane (3 mL) and
ethanol (1.5 mL). A solution of HCl in ethanol (5%, 0.5 mL) was
added, and the solution was stirred overnight. The reaction mixture
was concentrated under reduced pressure, and the residue was
purified by flash chromatography eluting with ethyl acetate and
light petroleum (3:7) to give the title compound as a colorless
crystalline solid (45 mg, 86%); mp 209-210 °C (from light
petroleum/ethyl acetate); IR (CHCl3/cm-1) 3427, 2941, 1736, 1668,
1
1619, 1455, 1374, 1306, 1128, 997; H NMR (400 MHz; CDCl3)
δ 7.68 (1 H, s), 7.48 (1 H, d, J 8.4), 7.36-7.31 (6 H, m), 7.05 (1
H, t, J 7.8), 3.21 (3 H, s), 3.20 (3 H, s); 13C NMR (100 MHz;
CDCl3) δ 173.7 (C), 169.3 (C), 141.2 (C), 135.6 (C), 131.9 (CH),
128.8 (C), 128.5 (CH), 128.23 (CH), 128.17 (CH), 124.7 (CH),
123.7 (CH), 102.9 (C), 64.9 (C), 59.8 (Me), 33.5 (Me); MS (ES)
399:397 (M + Na+, 100:99%), 377:375 (MH+, 70:75); Found:
MH+, 375.0330. C17H1579BrN2O3 + H requires: 375.0339.
2-[2-(4-Methoxybenzyloxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane 7. (a) To a suspension of 2-iodophenol (2.23 g,
10 mmol), potassium carbonate (1.65 g, 12 mmol), tetra-n-
butylammonium iodide (184 mg, 0.5 mmol), and 18-crown-6
(176 mg, 0.66 mmol) in acetone (50 mL) was added 4-methoxy-
benzyl chloride (1.49 mL, 11 mmol). The resulting suspension was
stirred rapidly at reflux overnight. The solvent was removed in
vacuo, and the residue was partitioned between water and ethyl
acetate (2 × 100 mL). The aqueous layer was extracted with ethyl
1
1513, 1329, 1240, 1173, 1108, 1025, 1007; H NMR (400 MHz;
CDCl3) δ 9.16 (1 H, s), 7.54 (1 H, d, J 8.0), 7.45-7.40 (2 H, m),
7.39-7.33 (2 H, m), 7.15-7.12 (1 H, m), 7.10-7.05 (4 H, m),
6.74 (2 H, d, J 8.8), 4.95 (2 H, s), 4.23 (2 H, q, J 7.2), 3.73 (3 H,
s), 1.14 (3 H, t, J 7.2); 13C NMR (100 MHz; CDCl3) δ 162.1 (C),
158.9 (C), 156.7 (C), 135.7 (C), 132.1 (CH), 129.3 (C), 128.7 (CH),
128.4 (CH), 128.2 (C), 125.3 (CH), 124.0 (C), 123.7 (C), 122.0
(CH), 120.5 (CH), 120.4 (CH), 120.0 (C), 113.6 (CH), 113.0 (CH),
111.6 (CH), 70.1 (CH2), 60.6 (CH2), 55.1 (Me), 13.9 (Me); MS
(ESI) 424 (M + Na+, 100%), 402 (MH+, 51%); Found: MH+,
402.1677. C25H23NO4 + H requires: 402.1705. Found: C, 74.48;
H, 5.80; N, 3.40. C25H23NO4 requires: C, 74.79; H, 5.77; N, 3.49%.
Ethyl 7-Bromo-3-[2-(4-methoxybenzyloxy)phenyl]indole-2-
carboxylate 8b. To a degassed solution of ethyl 7-bromo-3-
iodoindole-2-carboxylate 6b (300 mg, 0.76 mmol) and PdCl2(dppf)
(66) Lachia, M.; Poriel, C.; Slawin, A. M. Z.; Moody, C. J. Chem.
Commun. 2007, 286.
2982 J. Org. Chem., Vol. 72, No. 8, 2007

OxidatiVe Rearrangement of Indoles
‚CH2Cl2 (117 mg, 0.16 mmol) in DME (10.5 mL) was added under
nitrogen 2-[2-(4-methoxybenzyloxy)phenyl]-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane 7 (130 mg, 0.38 mmol), followed by a solution
of potassium carbonate (525 mg, 3.81 mmol) in water (1.5 mL).
The resulting mixture was degassed and heated to 30 °C for 2 h,
and more borolane (260 mg, 0.76 mmol) was then gradually added
over 3 h. The reaction mixture was stirred for 20 h and poured
into saturated aqueous ammonium chloride (7 mL). Dichlo-
romethane (20 mL) and water (20 mL) were added, and the residual
aqueous solution was extracted with dichloromethane (3 × 20 mL).
The combined organic layers were dried (MgSO4), evaporated in
vacuo, and purified by column chromatography on silica, eluting
with ethyl acetate/light petroleum (1:9) to give the title compound
as a colorless oil (150 mg, 41%); IR (CH2Cl2/cm-1) 3434, 2938,
156.7 (C), 140.4 (C), 131.4 (CH), 130.1 (C), 129.8 (CH), 129.5
(CH), 128.7 (CH), 128 (C), 125.2 (C), 124.7 (CH), 123.7 (CH),
120.8 (CH), 113.9 (CH), 112.9 (CH), 102.5 (C), 70.5 (CH2), 64.3
(C), 62.3 (CH2), 55.2 (Me), 13.8 (Me); MS (EI) 497:495 (M+, 27:
54%), 338 (30), 337 (100), 330:328 (18:12), 206:204 (12:29), 121
(17), 106 (40), 83 (39); Found: M+, 495.0699. C25H2279BrNO5
requires: 495.0681.
Ethyl 1-(tert-Butoxycarbonyl)-3-[2-(4-methoxybenzyloxy)phe-
nyl]-2-oxoindole-3-carboxylate 10a. A suspension of ethyl 3-[2-
(4-methoxybenzyloxy)phenyl]-2-oxoindole-3-carboxylate 9a (270
mg, 0.64 mmol), sodium carbonate (342 mg, 3.23 mmol), and di-
tert-butyl dicarbonate (352 mg, 1.61 mmol) in anhydrous THF (15
mL) was stirred at reflux for 3 h. Water (20 mL) was added, and
the reaction mixture was extracted with ethyl acetate (3 × 15 mL).
The combined organic layers were washed with brine, dried over
Na2SO4, filtered, and concentrated. The residue was purified by
flash chromatography eluting with light petroleum/ethyl acetate (8:
2) to give the title compound as a colorless solid (320 mg, 97%);
mp 142-144 °C (from light petroleum/chloroform); IR (CHCl3/
cm-1) 2982, 2937, 2838, 1799, 1795, 1731, 1613, 1586, 1465, 1454,
1
1724, 1698, 1515, 1313, 1230, 1033, 720; H NMR (300 MHz;
CDCl3) δ 8.95 (1 H, s), 7.42-7.22 (4 H, m), 7.03-6.89 (5 H, m),
6.67 (2 H, d, J 8.6), 4.86 (2 H, s), 4.14 (2 H, m), 3.68 (3 H, s),
1.04 (3 H, t, J 7.2); 13C NMR (75 MHz; CDCl3) δ 162.0 (C), 159.4
(C), 157.0 (C), 134.9 (C), 132.4 (CH), 129.6 (C), 129.5 (C), 129.4
(CH), 128.9 (CH), 128.0 (CH), 125.1 (C), 123.6 (C), 122.0 (CH),
121.7 (CH), 121.4 (C), 120.9 (CH), 114.0 (CH), 113.4 (CH), 105.4
(C), 70.5 (CH2), 61.3 (CH2), 55.6 (Me), 14.4 (Me); MS (FI) 481:
479 (M+, 100:96%), 338 (5), 337 (20), 121 (4); Found: M+,
479.0725. C25H2279BrNO4 requires: 479.0732.
1
1370, 1346, 1303, 1148, 1090, 1037, 1003; H NMR (400 MHz;
CDCl3) δ 7.78 (1 H, d, J 7.9), 7.36-7.32 (2 H, m), 7.27 (1 H, ddd,
J 8.2, 7.5, 1.7), 7.24-7.21 (2 H, m), 7.15 (1 H, ddd, J 7.5, 7.3,
1.0), 7.01 (1 H, dd, J 7.8, 1.6), 6.98 (1 H, dd, J 8.2, 0.8), 6.90-
6.84 (3 H, m), 4.96 (2 H, d, J 2.9), 4.04-3.90 (2 H, m), 3.81 (3 H,
s), 1.61 (9 H, s), 1.08 (3 H, t, J 7.1); 13C NMR (100 MHz; CD2-
Cl2) δ 170.2 (C), 168.3 (C), 159.2 (C), 156.8 (C), 149.1 (C), 140.1
(C), 129.8 (CH), 129.3 (CH), 129.0 (CH), 128.9 (CH), 128.4 (C),
127.0 (C), 125.9 (C), 125.4 (CH), 124.4 (CH), 120.6 (CH), 114.9
(CH), 113.7 (CH), 113.2 (CH), 84.1 (C), 70.5 (CH2), 62.7 (C), 62.1
(CH2), 55.2 (Me), 28.0 (Me), 13.7 (Me); MS (ESI) 540 (M + Na+,
100%), 518 (MH+, 2%), 418 (17%); Found: MH+, 518.2168.
C30H31NO7 + H requires: 518.2173.
Ethyl 3-[2-(4-Methoxybenzyloxy)phenyl]-2-oxoindole-3-car-
boxylate 9a. To a solution of ethyl 3-[2-(4-methoxybenzyloxy)-
phenyl]indole-2-carboxylate 8a (401 mg, 1.0 mmol) in dichlo-
romethane (30 mL) protected from the light was added tert-butyl
hypochlorite (183 mg, 1.5 mmol). The solution was stirred at room
temperature for 4 h before the solvents were removed in vacuo.
The residue was dissolved in dichloromethane (30 mL) and ethanol
(20 mL), and a solution of HCl in diethyl ether (1 M; 1.0 mL) was
added. The solution was stirred overnight. The solvents were
removed in vacuo, and the residue was purified by flash chroma-
tography eluting with light petroleum/ethyl acetate (4:1) to give
the title compound as a colorless solid (360 mg, 87%); mp 160-
161 °C (from light petroleum); IR (CHCl3/cm-1) 3435, 2936, 2838,
1747, 1614, 1453, 1317, 1310, 1095, 1038, 1002; 1H NMR
(400 MHz; CDCl3) δ 7.89 (1 H, s), 7.35-7.26 (4 H, m), 7.23 (1
H, dt, J 1.2, 7.8), 7.06-6.99 (3 H, m), 6.92-6.88 (3 H, m), 6.77
(1 H, d, J 7.8), 4.98 (2 H, s), 4.04-3.85 (2 H, m), 3.79 (3 H, s),
1.03 (3 H, t, J 7.1); 13C NMR (100 MHz; CDCl3) δ 175.0 (C),
168.4 (C), 159.2 (C), 157.0 (C), 141.4 (C), 129.5 (CH), 129.3 (CH),
128.9 (CH), 128.7 (CH), 128.6 (C), 126.0 (C), 125.8 (CH), 122.5
(CH), 120.8 (CH), 113.7 (CH), 113.1 (CH), 109.9 (CH), 70.5 (CH2),
63.0 (C), 61.9 (CH2), 55.2 (Me), 13.7 (Me); one C unobserved;
MS (ESI) 440 (MH+, 100%), 287 (9%); Found: MH+, 440.1457.
C25H23NO5 + H requires: 440.1468. Found: C, 71.87; H, 5.64;
N, 3.28. C25H23NO5 requires: C, 71.93; H, 5.55; N, 3.36%.
Ethyl 7-Bromo-3-[2-(4-methoxybenzyloxy)phenyl]-2-oxoin-
dole-3-carboxylate 9b. To a solution of ethyl 7-bromo-3-[2-(4-
methoxybenzyloxy)phenyl]indole-2-carboxylate 8b (78 mg, 0.16
mmol) protected from light in dichloromethane (3 mL) was added
a solution of tert-butyl hypochlorite (35 mg, 0.32 mmol) in
dichloromethane (3 mL). The solution was stirred at room tem-
perature for 2 h. Further tert-butyl hypochlorite (26 mg, 0.24 mmol)
was added, and the reaction mixture was stirred for a further 3 h.
The solvent was removed in vacuo, and the residue was dissolved
in dichloromethane (4 mL) and ethanol (2 mL). A total of 500 µL
of a solution of acetyl chloride (0.5 mL) in ethanol (9.5 mL) was
added, and the resulting mixture was stirred overnight, protected
from light. The solvent was removed in vacuo, and the residue was
purified by column chromatography eluting with ethyl acetate/light
petroleum (3:7) to give the title compound as a colorless solid (40
10-tert-Butyl 4b-Ethyl 9a,10-Dihydro-10-aza-9-oxaindeno[1,2-
a]indene-4b,10-dicarboxylate 11a. To a solution of ethyl 1-(tert-
butoxycarbonyl)-3-[2-(4-methoxybenzyloxy)phenyl]-2-oxoindole-
3-carboxylate 10a (270 mg, 0.52 mmol) in anhydrous THF (6 mL)
was added slowly at 0 °C a solution of sodium borohydride
(38 mg, 1.04 mmol) in MeOH (4 mL). The solution was stirred at
0 °C for 30 min before the careful addition of a solution of sulfuric
acid (0.5 M, 1.5 mL). Water (20 mL) was added, and the reaction
mixture was extracted with ether (3 × 20 mL). The combined
organic layers were washed with brine, dried (MgSO4), and filtered,
and the solvents were removed in vacuo. The residue was taken
up in dry dichloromethane (10 mL), triethylamine (215 µL,
1.56 mmol) was added under nitrogen, and the solution was cooled
to 0 °C. Then, methanesulfonic anhydride (135 mg, 0.78 mmol)
was added portion-wise over 15 min. A saturated solution of sodium
hydrogen carbonate (20 mL) was added at 0 °C, and the reaction
mixture was extracted with dichloromethane (3 × 20 mL). The
combined organic layers were washed with brine, dried over
MgSO4, and filtered, and the solvents were removed in vacuo. The
residue was purified by flash chromatography eluting with light
petroleum/ethyl acetate (24:1) to afford the title compound as a
colorless oil (141 mg, 76%); IR (CHCl3/cm-1) 2982, 2932, 1733,
1713, 1603, 1484, 1387, 1370, 1358, 1303, 1154, 1101, 1057, 1024,
907; 1H NMR (400 MHz; CDCl3) δ 7.79 (1 H, br), 7.67 (1 H, dd,
J 7.62, 1.1), 7.63 (1 H, dd, J 7.7, 0.9), 7.26 (1 H, ddd, J 8.2, 7.9,
1.3), 7.19 (1 H, ddd, J 8.1, 7.6, 1.4), 7.14 (1 H, br), 7.05 (1 H,
ddd, J 7.6, 7.6, 1.0), 6.95 (1 H, ddd, J 7.5, 7.5, 1.0), 6.84 (1 H, d,
J 8.0), 4.28 (2 H, q, J 7.1), 1.64 (9 H, s), 1.33 (3 H, t, J 7.1); 13C
NMR (100 MHz; CDCl3) δ 168.9 (C), 158.1 (C), 151.9 (C), 140.8
(C), 129.6 (CH), 128.3 (CH), 126.5 (C), 124.1 (2 × CH), 123.4
(CH), 121.4 (CH), 115.3 (CH), 113.8 (C), 110.2 (CH), 98.3 (CH),
82.5 (C), 63.4 (C), 62.3 (CH2), 28.3 (Me), 14.0 (Me); MS (ESI)
404 (M + Na+, 49%), 382 (MH+, 11%), 326 (75%), 282 (100%),
236 (55%); Found: MH+, 382.1668. C22H23NO5 + H requires:
382.1654. Found: C, 69.52; H, 6.15; N, 3.64. C22H23NO5 requires
C, 69.28; H, 6.08; N, 3.67%.
mg, 51%); mp 144-146 °C (light petroleum); IR (CH2Cl2/cm-1
)
3413, 2938, 1757, 1614, 1516, 1492, 1474, 1454, 1304, 1229, 1112,
1
1035; H NMR (300 MHz; CDCl3) δ 7.32-6.80 (12 H, m), 4.85
(2 H, s), 4.04-3.90 (2 H, m), 3.75 (3 H, s), 1.05 (3 H, t, J 7.0);
13C NMR (75 MHz; CDCl3) δ 172.9 (C), 167.8 (C), 159.4 (C),
J. Org. Chem, Vol. 72, No. 8, 2007 2983

Poriel et al.
Ethyl 1-Allyloxycarbonyl-3-[2-(4-methoxybenzyloxy)phenyl]-
2-oxoindole-3-carboxylate 10b. To a suspension of sodium hydride
(60% dispersion in mineral oil; 50 mg, 1.25 mmol) in dry THF
(15 mL) was added slowly at 0 °C under nitrogen a solution of
ethyl 3-[2-(4-methoxybenzyloxy)phenyl]-2-oxoindole-3-carboxylate
9a (180 mg, 0.42 mmol) in THF (5 mL). The suspension was stirred
for 5 min at 0 °C and then for 10 min at room temperature. Allyl
chloroformate (78 µL, 0.71 mmol) in dichloromethane (1 mL) was
added dropwise to the suspension at 0 °C. The solution was stirred
for 10 min at room temperature before the slow addition of
4-dimethylaminopyridine (30 mg, 0.25 mmol) in dichloromethane
(1 mL). After stirring for 5 min at room temperature, the reaction
mixture was cooled down again to 0 °C, and water (15 mL) was
added dropwise. The reaction mixture was extracted with diethyl
ether (3 × 20 mL), and the combined organic layers were washed
with brine, dried (MgSO4), and concentrated. The residue was
purified by flash chromatography eluting with light petroleum/ethyl
acetate (4:1) to give the title compound as a colorless oil (191 mg,
90%); IR (CHCl3/cm-1) 2930, 1782, 1731, 1613, 1465, 1368, 1342,
1302, 1156, 1091, 1038, 908; 1H NMR (400 MHz; CDCl3) δ 7.83
(1 H, d, J 8.1), 7.35 (1 H, ddd J 8.3, 8.2, 1.3), 7.31-7.27 (2 H, m),
7.20-7.15 (3 H, m), 7.07, (1 H, d, J 7.0), 6.97 (1 H, d, J 7.8), 6.91
(1 H, ddd, J 7.7, 7.6, 0.9), 6.87-6.83 (2 H, m), 6.02 (1 H, dddd,
J 17.0, 10.4, 5.6, 5.6), 5.52 (1 H, d, J 17.0), 5.33 (1 H, d, 10.4),
4.90 (2 H, s), 4.81 (2 H, d, J 5.4), 4.11-3.93 (2 H, m), 3.82 (3 H,
s), 1.10 (3 H, t, J 7.1); 13C NMR (100 MHz; CDCl3) δ 170.0 (C),
167.7 (C), 159.3 (C), 156.6 (C), 150.5 (C), 139.6 (C), 131.1 (CH),
129.0 (CH), 129.4 (CH), 129.1 (CH), 128.9 (CH), 128.1 (C), 127.1
(C), 125.6 (C), 125.4 (CH), 124.7 (CH), 120.6 (CH), 119.0 (CH2),
115.0 (CH), 113.7 (CH), 112.9 (CH), 70.4 (CH2), 67.4 (CH2), 62.7
(C), 62.3 (CH2), 55.2 (Me), 13.7 (Me); MS (ESI) 524 (M + Na+,
100%); Found: M + Na+, 524.1660. C29H27NO7 + Na requires:
524.1685.
366.1336. C21H19NO5 + Na requires: 366.1342. Found: C, 68.76;
H, 5.27; N, 3.77. C21H19NO5 requires: C, 69.03; H, 5.24; N, 3.83%.
Ethyl 1-Allyloxycarbonyl-7-bromo-3-[2-(4-methoxybenzylox-
y)phenyl]-2-oxoindole-3-carboxylate 10c. To a solution of ethyl
7-bromo 3-[2-(4-methoxybenzyloxy)phenyl]-2-oxoindole-3-carbox-
ylate 9b (20 mg, 0.04 mmol) in THF (3 mL) was added at 0 °C
sodium hydride (60% dispersion in mineral oil, 6 mg, 0.15 mmol)
in one portion under nitrogen. The suspension was stirred for 5
min at 0 °C and then warmed to room temperature, stirred for 10
min, and then cooled to 0 °C. Allyl chloroformate (8 mg, 0.07
mmol) in dichloromethane (2 mL), was added dropwise over 5 min.
The suspension was warmed to room temperature and stirred for
10 min, and a solution of 4-dimethylaminopyridine (4 mg,
0.03 mmol) in dichloromethane (1 mL) was added dropwise over
5 min. The reaction mixture was stirred for a further 45 min and
then quenched with acetic acid (1 mL) at 0 °C. The mixture was
poured into a saturated aqueous sodium hydrogen carbonate
(10 mL) and extracted with diethyl ether (4 × 20 mL). The organic
layers were then washed sequentially with sulfuric acid (1 M), a
saturated solution of sodium hydrogen carbonate water, dried
(MgSO4), evaporated in vacuo, and purified by column chroma-
tography eluting with ethyl acetate/light petroleum (3:7) to give
the title compound as a colorless oil (16 mg, 69%); IR (CH2Cl2/
cm-1) 2938, 1799, 1742, 1612, 1515, 1490, 1463, 1446, 1363, 1285,
1
1222, 1176, 1159, 1110, 1026, 941; H NMR (300 MHz; CDCl3)
δ 7.43 (1 H, d, J 8.1), 7.23-6.75 (10 H, m), 5.92 (1 H, ddt, J 17.1,
10.5, 5.8), 5.36 (1 H, dd, J 17.3, 1.3), 5.24 (1 H, dd, J 10.3, 1),
4.88 (2 H, s), 4.80 (2 H, d, J 5.9), 4.01-3.81 (2 H, m), 3.72 (3 H,
s), 1.03 (3 H, t, J 7.0); 13C NMR (100 MHz; CDCl3) δ 170.4 (C),
167.1 (C), 159.1 (C), 156.3 (C), 149.3 (C), 138.7 (C), 133.8 (CH),
130.7 (C), 130.6 (CH), 129.9 (CH), 129.0 (CH), 128.8 (CH), 128.2
(C), 125.6 (CH), 124.8 (C), 124.5 (CH), 120.6 (CH), 119.6 (CH2),
113.7 (CH), 113.0 (CH), 106.7 (C), 70.2 (CH2), 68.7 (CH2), 64.3
(C), 62.5 (CH2), 55.1 (Me), 13.5 (Me); MS (FI) 581/579 (M+, 94:
100%), 106 (25); Found: M+, 579.0908. C29H2679BrNO7 requires:
579.0893.
10-Allyl 4b-Ethyl 9a,10-Dihydro-10-aza-9-oxaindeno[1,2-a]-
indene-4b,10-dicarboxylate 11b. To a solution of ethyl 1-ally-
loxycarbonyl-3-[2-(4-methoxybenzyloxy)phenyl]-2-oxoindole-3-
carboxylate 10b (190 mg, 0.38 mmol) in anhydrous THF (5 mL)
was added slowly at 0 °C a solution of sodium borohydride
(29 mg, 0.76 mmol) in MeOH (3.5 mL). The solution was stirred
at 0 °C for 30 min before the careful addition of a solution of
sulfuric acid (0.5 M, 1 mL). Water (20 mL) was added, and the
reaction mixture was extracted with ether (3 × 20 mL). The
combined organic layers were washed with brine, dried over
MgSO4, and filtered, and the solvents were removed in vacuo. The
residue was taken up with dry dichloromethane (5 mL), triethy-
lamine (157 µL, 1.14 mmol) was added under nitrogen, and the
solution was cooled to 0 °C. Then, methanesulfonic anhydride
(99 mg, 0.57 mmol) was added portion-wise over 15 min. Saturated
aqueous sodium hydrogen carbonate (10 mL) was added at 0 °C,
and the reaction mixture was extracted with dichloromethane (3 ×
20 mL). The combined organic layers were washed with brine, dried
(MgSO4), and filtered, and the solvents were removed in vacuo.
The residue was purified by flash chromatography eluting with light
petroleum/ethyl acetate (19:1) to afford the title compound as a
colorless oil (87 mg, 63%); IR (CHCl3/cm-1) 2983, 1731, 1603,
10-Allyl 4b-Ethyl 9a,10-Dihydro-10-aza-9-oxa-1-bromoin-
deno[1,2-a]indene-4b,10-dicarboxylate 11c. To a solution of ethyl
1-allyloxycarbonyl-7-bromo-3-[2-(4-methoxybenzyloxy)phenyl]-2-
oxoindole-3-carboxylate 10c (20 mg, 34 µmol) in THF (3 mL) was
added at 0 °C under a nitrogen atmosphere a solution of sodium
borohydride (6 mg, 158 µmol) dissolved at 0 °C in methanol. The
reaction mixture was stirred for a further 45 min, poured into a
stirred solution of sulfuric acid (1 M, 5 mL), and extracted with
ether (4 × 20 mL). The organic layers were washed with saturated
aqueous sodium hydrogen carbonate, water, dried (MgSO4), and
evaporated in vacuo. The residue was taken up in dichloromethane
(3 mL), and triethylamine (40 µL, 285 µmol) was added, followed
by methanesulfonic anhydride (72 mg, 414 µmol) in one portion.
The resulting mixture was stirred for 24 h and was poured into a
solution of sodium hydrogen carbonate (10%, 5 mL) and extracted
with dichloromethane (3 × 20 mL). The organic layers were washed
with water, dried (MgSO4), evaporated in vacuo, and purified by
column chromatography eluting with ethyl acetate/light petroleum
(3:7) to give the title compound as a colorless oil (9 mg, 60%); IR
(CH2Cl2/cm-1) 2962, 2930, 1738, 1600, 1477, 1465, 1446, 1381,
1369, 1297, 1217, 1098, 1028; 1H NMR (300 MHz; CDCl3) δ 7.60
(1 H, dd, J 7.5, 1.3), 7.42 (2 H, td, J 7.7, 1.0), 7.13 (1 H, td, J 7.5,
1.0), 7.11 (1 H, s), 6.94 (1 H, t, J 7.7), 6.88 (1 H, td, J 7.5, 1.0),
6.77 (1 H, d, J 7.5), 5.99 (1 H, ddt, J 17.1, 10.3, 5.8), 5.36 (1 H,
ddt, J 17.3, 1.5, 1.3), 5.24 (1 H, ddt, J 10.3, 1.5, 1.3), 4.82 (1 H,
ddt, J 13, 5.8, 1.3), 4.76 (1 H, ddt, J 13, 5.8, 1.3), 4.21 (2 H, q, J
7.2), 1.26 (3 H, t, J 7.2); 13C NMR (100 MHz; CDCl3) δ 167.9
(C), 157.9 (C), 152.2 (C), 139.7 (C), 134.6 (C), 134.2 (CH), 131.5
(CH), 129.8 (CH), 126.7 (CH), 125.4 (C), 124.1 (CH), 123.1 (CH),
121.6 (CH), 118.9 (CH2), 112.1 (C), 110.0 (CH), 100.4 (CH), 67.5
(CH2), 64.0 (C), 62.4 (CH2), 13.8 (Me); MS (FI) 445:443 (M+,
100%), 337 (70), 338 (25); Found: M+, 443.0353. C21H1879BrNO5
requires: 443.0368.
1
1485, 1395, 1347, 1298, 1153, 1102, 1058, 1030, 993, 945; H
NMR (400 MHz; CDCl3) δ 7.85 (1 H, br), 7.69 (1 H, dd, J 7.6,
1.2), 7.66 (1 H, ddd, J 7.6, 1.3, 0.5), 7.29 (1 H, ddd, J 8.2, 7.8,
1.3), 7.21 (1 H, s), 7.20 (1 H, ddd, J 8.0, 7.5, 1.3), 7.08 (1 H, ddd,
J 7.6, 7.5, 1.0), 6.96 (1 H, ddd, J 7.6, 7.5, 1.0), 6.85 (1 H, d, J
8.0), 6.10 (1 H, dddd, J 17.2, 10.6, 5.5, 5.5), 5.50 (1 H, d, J 17.2),
5.34 (1 H, ddd, J 10.5, 2.6, 1.3), 4.87 (2 H, m), 4.29 (2 H, q, J
7.1), 1.33 (3 H, t, J 7.1); 13C NMR (100 MHz; CDCl3) δ 169.3
(C), 158.5 (C), 152.8 (C), 141.3 (C), 132.7 (CH), 130.5 (CH), 130.1
(CH), 127.1 (C), 124.97 (CH), 124.88 (CH), 124.5 (CH), 122.3
(CH), 118.8 (CH2), 115.9 (CH), 110.7 (CH), 98.8 (CH), 67.4 (CH2),
64.0 (C), 63.2 (CH2), 14.5 (Me); one C unobserved; MS (ESI) 388
(M + Na+, 20%), 366 (MH+, 100), 320 (25); Found: M + Na+,
2984 J. Org. Chem., Vol. 72, No. 8, 2007

OxidatiVe Rearrangement of Indoles
10-tert-Butoxycarbonyl-9a,10-dihydro-10-aza-9-oxaindeno-
[1,2-a]indene-4b-carboxylic Acid 12a. To a solution 10-tert-butyl
4b-ethyl 10-aza-9-oxaindeno[1,2-a]indene-4b,10-dicarboxylate 11a
(72 mg, 0.188 mmol) in ethanol (2.5 mL) was added a solution of
cesium carbonate (66 mg, 0.20 mmol) in water (4 mL). The milky
suspension was stirred at room temperature for 48 h. The clear
reaction mixture was concentrated in vacuo, water was added
(4 mL), and the pH was adjusted to 1 using hydrochloric acid (2
M). The precipitate was filtered, washed with cold water, and dried
in vacuo. The title compound was obtained as a powder (55 mg,
83%); mp 98-100 °C (light petroleum/chloroform); IR (CHCl3/
cm-1) 3198, 2981, 1754, 1715, 1603, 1484, 1387, 1370, 1358, 1303,
1154, 1102, 1057, 1021, 967, 945, 866; 1H NMR (400 MHz;
CDCl3) δ 7.82 (1 H, br), 7.66 (1 H, d, J 7.5), 7.62 (1 H, d, J 7.5),
7.26 (1 H, t, J 7.7), 7.20-7.15 (2 H, m), 7.03 (1 H, t, J 7.5), 6.93
(1 H, t, J 7.5), 6.86 (1 H, d, J 8.0), 1.65 (9 H, s); OH not observed;
13C NMR (100 MHz; CDCl3) δ 174.5 (C), 158.0 (C), 140.8 (C,
br), 129.9 (CH), 129.6 (CH), 128.8 (C, br), 125.8 (C), 124.3 (CH),
123.5 (CH), 121.6 (CH), 115.4 (CH), 110.3 (CH), 98.1 (CH), 82.9
(C, br), 63.6 (C, br), 28.3 (Me); MS (FI) 376 (M + Na+, 100%),
320 (23%), 254 (15%); Found: M + Na+, 376.1153. C20H19NO5
+ Na requires: 376.1160.
oxaindeno[1,2-a]indene-4b,10-dicarboxylate 11a (95 mg,
0.25 mmol) in dichloromethane (5 mL) was added trifluoroacetic
acid (0.40 mL). The solution was stirred overnight at room
temperature, and a saturated solution of sodium hydrogen carbonate
(10 mL) was carefully added. The aqueous layer was extracted with
dichloromethane (3 × 10 mL), and the combined organic layers
were dried (Na2SO4), filtered, and concentrated in vacuo. The
residue was purified by flash chromatography eluting with light
petroleum/ethyl acetate (9:1) to give the title compound as a
colorless solid (36 mg, 51%); mp 115-117 °C (from light
petroleum); IR (CHCl3/cm-1) 3450, 1731, 1609, 1485, 1319, 1051;
1H NMR (400 MHz; CDCl3) δ 7.67 (1 H, ddd, J 7.6, 1.4, 0.4),
7.58 (1 H, ddd, J 7.6, 1.3, 0.5), 7.18 (1 H, ddd, J 8.0, 7.5, 1.4),
7.13 (1 H, ddd, J 7.8, 7.7, 1.3), 6.93 (1 H, ddd, J 7.5, 7.5, 1.0),
6.89 (1 H, d, J 2.7), 6.85-6.81 (2 H, m), 6.69 (1 H, d, J 7.9), 5.10
(1 H, br), 4.30 (2 H, q, J 7.1), 1.36 (3 H, t, J 7.1); 13C NMR (100
MHz; CDCl3) δ 169.6 (C), 158.2 (C), 147.2 (C), 129.4 (CH), 129.3
(CH), 127.5 (C), 126.9 (C), 124.4 (CH), 124.2 (CH), 121.1 (CH),
119.9 (CH), 110.1 (CH), 109.7 (CH), 99.9 (CH), 65.8 (C), 62.1
(CH2), 14.1 (Me); MS (ES) 304 (M + Na+, 100%), 282 (MH+,
67%), 236 (52%); Found: MH+, 282.1116. C17H15NO3 + H
requires: 282.1125. Found: C, 72.29; H, 5.50; N, 4.83. C17H15-
NO3 requires: C, 72.58; H, 5.37; N, 4.98%.
10-Allyloxycarbonyl-9a,10-dihydro-10-aza-9-oxaindeno[1,2-
a]indene-4b-carboxylic Acid 12b. To a solution of 10-allyl 4b-
ethyl 10-aza-9-oxaindeno[1,2-a]indene-4b,10-dicarboxylate 11b
(25 mg, 0.068 mmol) in ethanol (2.5 mL) was added a solution of
cesium carbonate (66 mg, 0.20 mmol) in water (4 mL). The milky
suspension was stirred at room temperature for 48 h. The clear
reaction mixture was concentrated in vacuo, and water was added
(4 mL). The pH was adjusted to 1 using hydrochloric acid (2 M),
and the precipitate was extracted with dichloromethane (3 ×
10 mL). The combined organic layers were washed with brine, dried
(Na2SO4), and concentrated. The resulting powder was recry-
stallized from light petroleum and chloroform to give the title
compound as a colorless solid (21 mg, 91%); mp 164-166 °C (light
petroleum/chloroform); IR (CHCl3/cm-1) 2891, 1715, 1603, 1485,
(S)-N-Benzyloxycarbonyl-O-(4-methoxybenzyl)-3-iodoty-
rosine tert-Butyl Ester. To a suspension of N-benzyloxycarbonyl-
3-iodotyrosine tert-butyl ester 1546 (468 mg, 0.94 mmol), potassium
carbonate (156 mg, 1.13 mmol), 18-crown-6 (16.6 mg, 0.06 mmol),
and tetra-n-butylammonium iodide (17 mg, 0.05 mmol) in acetone
(50 mL) was added 4-methoxybenzyl chloride (141 µL, 1.04 mmol).
The resulting mixture was heated to reflux for 12 h. The solvent
was removed in vacuo, and the residue was taken up in dichlo-
romethane, washed with water (2 × 50 mL), brine (100 mL), dried
(MgSO4), and concentrated in vacuo. The residue was purified by
flash chromatography eluting with dichloromethane/ether (100:0
to 97:3) to give the title compound as a colorless oil (520 mg, 90%);
35
[R]D +49 (c 1, CH2Cl2); IR (CH2Cl2/cm-1) 3424, 2981, 2938,
1
1466, 1396, 1347, 1297, 1153, 1103, 1057, 1022, 975, 946; H
1720, 1613, 1514, 1488, 1353, 1276, 1245, 1175, 1154, 1040, 1005,
1
NMR (400 MHz; CDCl3) δ 7.89 (1 H, br), 7.68 (1 H, dd, J 0.8,
7.6), 7.64 (1 H, d, J 7.6), 7.28 (1 H, t, J 7.2), 7.22-7.18 (2 H, m),
7.07 (1 H, ddd, J 7.6, 0.8), 6.96 (1 H, td, J 7.6, 0.8), 6.87 (1 H, d,
J 8.4), 6.08 (1 H, dddd, J 17.2, 10.5, 5.6, 5.4). 5.49 (1 H, d, J
17.2), 5.34 (1 H, dd, J 1.2, 10.4), 4.89 (2 H, d, J 5.6); OH not
observed; 13C NMR (100 MHz; CDCl3) δ 174.1 (C), 157.9 (C),
140.0 (C), 131.9 (C), 130.1 (CH), 129.8 (CH), 128.7 (C), 125.5
(C), 124.3 (CH), 124.0 (CH), 121.8 (C), 118.6 (CH2), 115.5 (CH),
110.4 (CH), 97.8 (CH), 66.9 (CH2), 63.7 (C); MS (FI) 445/443
(M+, 100%), 337 (70), 338 (25); Found: MH+, 338.1014. C19H15-
NO5 + H requires: 338.1023.
717; H NMR (300 MHz; CDCl3) δ 7.50 (1 H, d, J 1.9), 7.36-
7.20 (7 H, m), 6.97 (1 H, d, J 8.1), 6.84 (2 H, d, J 8.8), 6.67 (1 H,
d, J 8.4), 5.20 (1 H, d, J 8.0), 5.02 (2 H, m), 4.97 (2 H, s), 4.40 (1
H, td, J 7.9, 6.0), 3.74 (3 H, s), 2.91 (2 H, br d, J 5.7), 1.33 (9 H,
s); 13C NMR (100 MHz; CDCl3) δ 170.3 (C), 159.3 (C), 156.3
(C), 155.5 (C), 140.3 (CH), 136.3 (C), 130.5 (C), 130.4 (CH), 128.7
(CH), 128.6 (CH), 128.5 (C), 128.2 (CH), 128.1 (CH), 113.9 (CH),
112.6 (CH), 86.8 (C), 82.6 (C), 70.8 (CH2), 66.9 (CH2), 55.3 (Me),
55.2 (CH), 37.0 (CH2), 28.0 (Me); MS (CI) 618 (MH+, 25%), 518
(46), 390 (17), 211 (20), 121 (100); Found: MH+, 618.1348.
C29H32INO6 + H requires: 618.1352.
2-(Indol-3-yl)-phenol 13. 10-tert-Butoxycarbonyl-9a,10-dihydro-
10-aza-9-oxaindeno[1,2-a]indene-4b-car boxylic acid 12a (10 mg,
28 µmol) was heated to 100 °C until the gas emission ceased. The
residue was purified by flash chromatography eluting with light
petroleum and ethyl acetate (8:2) to give the title compound as a
(S)-N-Benzyloxycarbonyl-O-(4-methoxybenzyl)-3-[4,4,5,5-tet-
ramethyl-1,3,2-dioxaborolan-2-yl] Tyrosine tert-Butyl Ester 16.
To a solution of N-benzyloxycarbonyl-O-(4-methoxybenzyl)-3-
iodotyrosine tert-butyl ester (683 mg, 1.11 mmol) and 2-(dicyclo-
hexylphosphino)biphenyl (78 mg, 0.22 mmol) in dry and degassed
dioxane (6 mL) was added nitrogen palladium(II) acetate (14 mg,
0.06 mmol) and triethylamine (617 µL, 4.43 mmol). The resulting
mixture was degassed. 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane
(481 µL, 3.31 mmol) was then added dropwise over 15 min, and
the resulting green-black mixture was heated to 85 °C for 30 min.
The reaction mixture was poured into saturated ammonium chloride
solution (10 mL) and extracted with ethyl acetate (4 × 20 mL).
The combined extracts were washed with water (10 mL), dried
(MgSO4), evaporated in vacuo, and purified by column chroma-
tography eluting with ethyl acetate/light petroleum (1:9 to 3:7) to
give the title compound as a yellow oil (480 mg, 70%); [R]D26 +40
(c 0.74, CH2Cl2); IR (CH2Cl2/cm-1) 3426, 2982, 2935, 1720, 1608,
1514, 1496, 1372, 348, 1243, 1241, 1175, 1146, 1071, 1035, 910;
1H NMR (300 MHz; CDCl3) δ 7.42 (2 H, d, J 8.5), 7.31-7.22 (6
H, m), 7.09 (1 H, d, J 8.3), 6.83 (2 H, d, J 8.5), 6.75 (1 H, d, J
8.5), 5.17 (1 H, d, J 7.9), 5.02 (2 H, s), 4.95 (2 H, s), 4.43 (1 H,
colorless oil (5.0 mg, 84%); (lit.,67 mp 135 °C); IR (CHCl3/cm-1
)
3530, 3473, 1482, 1456, 1347, 1094; 1H NMR (500 MHz; CDCl3)
δ 8.42 (1 H, s), 7.63 (1 H, dd, J 8.0, 1.0), 7.49 (1 H, dt, J 8.0, 7.0),
7.41 (1 H, dd, J 7.5, 1.5), 7.38 (1 H, d, J 2.8), 7.32-7.29 (2 H, m),
7.20 (1 H, ddd, J 8.0, 7.5, 1.0), 7.07 (1 H, dd, J 8.0, 1.0), 7.02 (1
H, dd, J 7.5, 1.5), 5.41 (1 H, s); 13C NMR (100 MHz; CDCl3) δ
153.4 (C), 136.4 (C), 130.8 (CH), 128.6 (CH), 126.3 (C), 123.1
(CH), 123.0 (CH), 120.8 (C), 120.6 (CH), 120.5 (CH), 119.8 (CH),
115.3 (CH), 112.0 (C), 111.5 (CH); MS (ES) 222 (M + Na+, 74%),
210 (MH+, 100%); Found: MH+, 210.0911. C14H11NO3 + H
requires: 210.0919.
Ethyl 9a,10-Dihydro-10-aza-9-oxaindeno[1,2-a]indene-4b-car-
boxylate 14. To a solution of 10-tert-butyl 4b-ethyl 10-aza-9-
(67) Saleha, S.; Khan, N. H.; Siddiqui, A. A.; Kidwai, M. M. Indian J.
Chem., Sect. B 1978, 16, 1122.
J. Org. Chem, Vol. 72, No. 8, 2007 2985

Poriel et al.
td, J 8, 6.2), 3.74 (3 H, s), 2.96 (2 H, br d, J 5.8), 1.33 (9 H, s),
1.26 (12 H, s); 13C NMR (75 MHz; CDCl3) δ 170.5 (C), 162.4
(C), 158.8 (C), 155.5 (C), 137.8 (CH), 136.3 (C), 133.5 (CH), 130.5
(CH), 129.6 (C), 129.2 (CH), 128.4 (CH), 128.2 (CH), 128.02 (CH),
127.98 (CH), 127.7 (C), 114.7 (CH), 113.9 (CH), 113.4 (CH), 112.3
(CH), 83.3 (C), 82.2 (C), 69.8 (CH2), 66.7 (CH2), 55.2 (Me + CH),
37.3 (CH2), 27.9 (Me), 24.95 (Me), 24.88 (Me); one ArC not
observed (C-B); MS (EI) 617 (M+, 10%), 466 (7), 121 (100), 91
(36); Found: M+, 617.3166. C35H4411BNO8 requires: 617.3160.
(S)-Ethyl 3-[5-(2-Benzyloxycarbonylamino-2-tert-butoxycar-
bonylethyl)-2-(4-methoxybenzyloxy)]phenyl-7-bromoindole-2-
carboxylate 17. To a solution of ethyl 7-bromo-3-iodoindole-2-
carboxylate 6b (465 mg, 1.18 mmol) and PdCl2(dppf)‚CH2Cl2
(136 mg, 0.19 mmol) in degassed DME (15.5 mL) was added
N-benzyloxycarbonyl-O-(4-methoxybenzyl)-3-[4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl]tyrosine tert-butyl ester 16 (364 mg, 0.59
mmol), followed by potassium carbonate (856 mg, 6.22 mmol)
dissolved in water (2.2 mL). The resulting mixture was degassed
and heated to 35 °C for 2 h, and more of the borolane (728 mg,
1.18 mmol) was then gradually added over 3 h. The reaction mixture
was stirred for 40 h at 35 °C, cooled to room temperature, and
poured into saturated aqueous ammonium chloride (10 mL).
Dichloromethane (25 mL) and water (25 mL) were added, and the
residual aqueous solution was extracted with dichloromethane
(4 × 25 mL). The combined extracts were dried (MgSO4),
evaporated in vacuo, and purified by column chromatography
eluting with ethyl acetate/light petroleum (3:7) to give the title
0.98 (3 H, 2 × t, J 7.0); diastereomeric ratio 1:1.4, determined
from the CMe3 group signal; 13C NMR (100 MHz; CDCl3) δ 172.5
(C), 170.4 (C), 167.6 (C), 159.4 (C), 155.8 (C), 155.6 (C), 140.3
(C), 136.3 (C), 131.4 (CH), 130.8 (CH), 130.5 (CH), 129.9 (CH),
129.5 (CH), 128.9 (C), 128.5 (CH), 128.4 (C), 128.1 (CH), 128.0
(C), 125.3 (C), 124.7 (CH), 123.9 (CH), 113.8 (CH), 112.8 (CH),
102.5 (C), 82.3 (C), 70.7 (CH2), 66.9 (CH2), 64.1 (C), 62.3 (CH2),
55.3 (Me), 54.9 (CH), 37.4 (CH2), 27.8 (Me), 13.7 (Me); several
of the carbon signals are doubled due to the presence of diastere-
oisomers; MS (ES) 797:795 (M + Na+, 100%), 792:790 (M +
NH4+, 36:34), 725:723 (13:20), 741:739 (17:14), 719:717 (19:16),
675:673 (29:20); Found: M + NH4+, 790.2330. C40H4179BrN2O9
+ NH4 requires: 790.2334.
Ethyl 1-Allyloxycarbonyl-3-[5-(2-benzyloxycarbonylamino-
2-tert-butoxycarbonylethyl)-2-(4-methoxybenzyloxy)]phenyl-7-
bromo-2-oxoindole-3-carboxylate. To a solution of ethyl 3-[5-
(2-benzyloxycarbonylamino-2-tert-butoxycarbonylethyl)-2-(4-
methoxybenzyloxy)]phenyl-7-bromo-2-oxoindole-3 carboxylate 18
(20 mg, 26 µmol) in THF (5 mL) cooled at 0 °C was added sodium
hydride (8 mg of 60% dispersion in mineral oil, 207 µmol) in one
portion under nitrogen. The suspension was stirred for 5 min at 0
°C and then warmed to room temperature, stirred for 15 min, and
then cooled down to 0 °C. A solution of allyl chloroformate
(13 mg, 108 µmol) in dichloromethane (2 mL) was added dropwise
over 5 min. The suspension was then warmed to room temperature
and stirred for 10 min, and a solution of 4-dimethylaminopyridine
(7 mg, 57 µmol) in dichloromethane (2 mL) was added dropwise
over 5 min. The reaction mixture was stirred for a further 2 h and
then quenched with acetic acid (1 mL) at 0 °C. The mixture was
poured into a saturated solution of sodium hydrogen carbonate
(10 mL) and extracted with diethyl ether (5 × 20 mL). The organic
layers were then washed sequentially with sulfuric acid (1 M),
saturated aqueous sodium hydrogen carbonate, water, dried (Mg-
SO4), evaporated in vacuo, and purified by column chromatography
eluting with ethyl acetate/light petroleum (3:7) to give the title
compound as a yellow oil (14 mg, 63%) as an inseparable mixture
of diastereoisomers; IR (CH2Cl2/cm-1) 2934, 1770, 1713 (shoulder
at 1740), 1612, 1515, 1497, 1460, 1369, 1359, 1232, 1212, 1170,
1151, 1110, 1027, 947; 1H NMR (300 MHz; CDCl3) δ 7.48-6.74
(15 H, m), 5.92:5.91 (1 H, 2 × ddt, J 17.1, 10.4, 5.9), 5.35 (1 H,
dd, J 17.3, 1.5), 5.21 (1 H, dd, J 10.3, 1.1), 5.14 (1 H, d, J 8.0),
5.02 (2 H, br s), 4.88-4.82 (2 H, m), 4.79 (2 H, d, J 5.9), 4.41-
4.34 (1 H, m), 4.02-3.79 (2 H, m), 3.75 (3 H, s), 2.90 (2 H, m, J
5.7), 1.26:1.24 (9 H, s), 1.02:0.98 (3 H, 2 × t, J 6.9); diastereomeric
ratio 1:1.4, determined from the CMe3 group signal; 13C NMR
(100 MHz; CDCl3) δ 170.0 (C), 169.6 (C), 167.7 (C), 159.1 (C),
155.2 (C), 149.3 (C), 138.8 (C), 136.3 (C), 131.5 (CH), 131.3 (CH),
130.0 (CH), 130.5 (CH), 129.8 (CH), 129.0 (CH), 128.5 (CH), 128.5
(C), 128.7 (C), 128.0 (CH), 127.9 (C), 124.7 (C), 125.6 (CH), 125.7
(CH), 119.8 (CH2), 113.6 (CH), 113.2 (CH), 110.1 (C), 106.7 (C),
82.3 (C), 70.4 (CH2), 68.5 (CH2), 66.9 (CH2), 64.1 (C), 62.5 (CH2),
55.2 (Me), 54.9 (CH), 37.4 (CH2), 27.8 (Me), 13.4 (Me); several
of the carbon signals are doubled due to the presence of diastere-
oisomers; MS (ES) 881:879 (M + Na+, 100%), 876:874 (M +
NH4+, 36:34), 759/:757 (36:32), 741:739 (17:14), 723:721 (20:14);
Found: M + NH4+, 874.2541. C44H4579BrN2O11 + NH4 requires:
874.2545.
compound as a yellow solid (350 mg, 40%); mp 60-68 °C (dec)
32
(light petroleum); [R]D + 28.4 (c 0.74, CH2Cl2); IR (film/cm-1
)
1
3430, 2981, 1722, 1637, 1514, 1309, 1231, 1174, 1155, 1033; H
NMR (300 MHz; toluene-d; 100 °C) δ 8.77 (1 H, s), 7.40 (1 H, t,
J 8.1), 7.24-6.95 (8 H, m), 6.84 (3 H, t, J 7.9), 6.70 (1 H, t, J
7.9), 6.66 (2 H, d, J 8.9), 5.09 (1 H, br d, J 8.1), 4.96 (2 H, m),
4.66 (2 H, s), 4.56 (1 H, td, J 6.2, 8.1), 4.02 (2 H, q, J 7.1), 3.32
(3 H, s), 3.03 (1 H, dd, J 6.1, 14.1), 2.99 (1 H, dd, J 6.1, 14.1),
1.27 (9 H, s), 0.87 (3 H, t, J 7.1); 13C NMR (100 MHz; DMSO-d;
60 °C) δ 170.5 (C), 160.6 (C), 158.4 (C), 154.6 (C), 136.6 (C),
134.3 (C), 131.9 (CH), 128.9 (CH), 128.8 (C), 128.75 (C), 128.7
(C), 128.6 (C), 128.3 (CH), 127.8 (CH), 127.2 (CH), 127.1 (CH),
127.0 (CH), 125.7 (C), 122.3 (C), 120.9 (CH), 120.2 (CH), 119.1
(C), 113.2 (CH), 112.5 (CH), 104.3 (C), 80.3 (C), 69.2 (CH2), 65.1
(CH2), 59.8 (CH2), 56.0 (CH), 54.7 (Me), 35.7 (CH2), 27.2 (Me),
13.3 (Me); MS (ES) 781/779 (M + Na+, 99/87%), 759:757 (MH+,
30/28), 725:723 (13:20), 703:701 (34:32), 659:657 (42:44), 640
(12), 530 (20), 518 (12); Found: MH+, 757.2122. C40H4179BrN2O8
+ H requires: 757.2119.
Ethyl 3-[5-(2-Benzyloxycarbonylamino-2-tert-butoxycarbonyl-
ethyl)-2-(4-methoxybenzyloxy)]phenyl-7-bromo-2-oxoindole-3-car-
boxylate 18. To a stirred solution of ethyl 3-[5-(2-benzyloxycar-
bonylamino-2-tert-butoxycarbonylethyl)-2-(4-methoxybenzyloxy)]-
phenyl-7-bromoindole-2 carboxylate 17 (140 mg, 0.18 mmol) in
dichloromethane (3 mL) protected from light was added tert-butyl
hypochlorite (42 mg, 0.39 mmol). The reaction was stirred under
nitrogen at room temperature for 2 h. tert-Butyl hypochlorite (42
mg, 0.39 mmol) was added again, and the reaction mixture was
stirred for a further 6 h. The solvent was removed in vacuo, and
the residue was dissolved in dichloromethane (14 mL) and ethanol
(7 mL). A total of 570 µL of a solution of acetyl chloride (0.5 mL)
in ethanol (9.5 mL) was added, and the resulting mixture was stirred
overnight, protected from light. The solvent was removed in vacuo,
and the residue was purified by column chromatography eluting
with ethyl acetate/light petroleum (3:7) to give the title compound
as a yellow solid (95 mg, 68%) as an inseparable mixture of
diastereoisomers; mp 88-93 °C (dec) (light petroleum); IR (CH2-
Cl2/cm-1) 3419, 2934, 1728 (shoulder at 1758), 1614, 1515, 1499,
1468, 1369, 1304, 1212, 1156, 1036; 1H NMR (300 MHz; CDCl3)
δ 7.28-6.74 (16 H, m), 5.17 (1 H, d, J 7.7), 5.01 (2 H, br s),
4.87-4.82 (2 H, m), 4.41-4.34 (1 H, m), 3.99-3.80 (2 H, m),
3.75 (3 H, s), 2.90 (2 H, br d, J 5.7), 1.26:1.24 (9 H, 2 × s), 1.02:
10-Allyl, 4b-Ethyl 6-(2-Benzyloxycarbonylamino-2-tert-bu-
toxycarbonylethyl)-1-bromo-9a,10-dihydro-10-aza-9-oxaindeno-
[1,2-a]indene-4b,10-dicarboxylate 19. Sodium borohydride (7 mg,
184 µmol) was dissolved in methanol (1 mL) at 0 °C and added at
0 °C to a solution of ethyl 1-allyloxycarbonyl-3-[5-(2-benzyl-
oxycarbonylamino-2-tert-butoxycarbonylethyl)-2-(4-methoxyben-
zyloxy)]phenyl-7-bromo-2-oxoindole-3-carboxylate (30 mg, 35
µmol) in THF (7 mL) under nitrogen. The reaction mixture was
stirred for a further 30 min, poured into a stirred solution of sulfuric
acid (1 M), and extracted with ether (5 × 20 mL). The organic
layers were washed with saturated aqueous sodium hydrogen
carbonate, water, dried (MgSO4), and evaporated in vacuo. The
2986 J. Org. Chem., Vol. 72, No. 8, 2007

OxidatiVe Rearrangement of Indoles
residue was taken up in dichloromethane (3 mL) and triethylamine
(50 µL, 360 µmol) was added, followed by methanesulfonic
anhydride (90 mg, 517 µmol), in one portion. The resulting mixture
was stirred for 52 h. The mixture was then poured into aqueous
sodium hydrogen carbonate (10%, 5 mL) and extracted with
dichloromethane (3 × 20 mL). The organic layers were washed
with water, dried (MgSO4), evaporated in vacuo, and purified by
column chromatography eluting with ethyl acetate/light petroleum
(3:7) to give the title compound as a colorless oil (10 mg, 40%) as
an inseparable mixture of diastereoisomers; IR (CH2Cl2/cm-1) 3426,
2982, 2935, 1735, 1606, 1507, 1489, 1446, 1370, 1340, 1231, 1156,
1123, 1060, 1029, 967; 1H NMR (300 MHz; CDCl3) δ 7.41-7.21
(7 H, m), 7.09 (1 H, s), 6.93-6.86 (2 H, m), 6.73 (1 H, t, J 7.9),
6.65 (1 H, d, J 8.3), 5.97 (1 H, ddt, J 17.1, 10.5, 5.6), 5.36 (1 H,
br dd, J 17.3, 1.1), 5.29 (1 H, br dd, J 10.3, 1.1), 5.17 (1 H, m),
5.02 (2 H, m), 4.78 (2 H, dd, J 13, 5.8), 4.49-4.38 (1 H, m), 4.22-
4.10 (2 H, m), 2.97 (2 H, br d, J 5.8), 1.30, (9 H, s), 1.22 (3 H, t,
J 7.2); 13C NMR (100 MHz; CDCl3) δ 170.5 (C), 168.0 (C), 157.1
(C), 155.5 (C), 152.4 (C), 139.8 (C), 136.2 (C), 134.6 (C), 134.4
(CH), 132.4 (CH), 131.6 (CH), 131.1 (CH), 130.0 (CH), 129.5 (C),
128.4 (CH), 128.2 (CH), 128.1 (CH), 127.0 (CH), 125.7 (C), 125.2
(CH), 123.3 (CH), 119.1 (CH2), 112.2 (C), 110.0 (CH), 100.8 (CH),
82.4 (C), 67.7 (CH2), 66.9 (CH2), 64.1 (C), 62.6 (CH2), 55.0 (CH),
37.7 (CH2), 27.9 (Me), 14.0 (Me); several of the carbon signals
are doubled due to the presence of diastereoisomers; MS (ES) 745:
743 (M + Na+, 69:61%), 740:738 (M + NH4+, 29:24), 689:687
(42:35), 667:665 (33:29), 623:621 (100:93), 579 (33), 577 (56),
79
575 (33), 533/531 (30/37); Found: M + NH4, 738.2019. C36H37
BrN2O9 + NH4 requires: 738.2021.
-
Acknowledgment. We thank the EPSRC and Tripos Recep-
tor Research (CASE award to J.R.D.) for funding, Dr. Peter
Kane for helpful discussions, and the EPSRC Mass Spectrometry
Center at Swansea for mass spectra.
Supporting Information Available: General experimental
details and the preparation of starting indoles 3a, 3b, 3c, 5b, 6a,
and 6b; X-ray crystal data for compounds 4c, 10a, and 14; and
copies of 1H and 13C NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO062627R
J. Org. Chem, Vol. 72, No. 8, 2007 2987