Synthesis of 8-desbromohinckdentine A

Article abstract of DOI:10.1021/ja021380m

Hinckdentine A is an alkaloid isolated from the bryozoan Hincksinoflustra denticulate. This natural product contains a novel and unique 11b, 12, 13, 14, 15, 16-hexahydroazepino[4′,5′:2,3]indolo[1,2-c]quinazoline ring system that has not previously been sy

Full text of DOI:10.1021/ja021380m

Published on Web 03/18/2003
Synthesis of 8-Desbromohinckdentine A1
Yahua Liu and William W. McWhorter, Jr.*
Contribution from Medicinal Chemistry Research, Pharmacia Corporation,
Kalamazoo, Michigan 49001
Received November 25, 2002 ; E-mail: william.w.mcwhorter@pharmacia.com
Abstract: Hinckdentine A is an alkaloid isolated from the bryozoan Hincksinoflustra denticulate. This natural
product contains a novel and unique 11b,12,13,14,15,16-hexahydroazepino[4′,5′:2,3]indolo[1,2-c]quinazoline
ring system that has not previously been synthesized. We have synthesized 8-desbromohinckdentine A
from a 2-aryl indole by first preparing the quaternary center of the natural product and then building the
seven-membered lactam and dihydropyrimidine rings onto this intermediate to form the framework of
hinckdentine A.
Scheme 1
Introduction
Hinckdentine A was isolated from the bryozoan Hincksino-
flustra denticulate, which was collected from the eastern coast
of Tasmania.2 Its structure and the absolute configuration were
determined by single-crystal X-ray methods.2 The natural
product contains a novel and unique 11b,12,13,14,15,16-
hexahydroazepino[4′,5′:2,3]indolo[1,2-c]quinazoline ring sys-
tem, a challenging synthetic target, that has not yet been
successfully synthesized. The biological activity of hinckdentine
A has apparently not been determined and is consequently not
described in the literature,2 but biologically important dihydro-
tryptamine and dihydropyrimidine units are contained within
the framework of the natural product.
Scheme 2
The indolo[1,2-c]quinazoline ring system was first prepared
in 1956 by Kiang and co-workers.3 Cava and Billimoria4a have
reviewed the chemistry of indoloquinazolines, which are
uncommon in nature. Moreover, they have published an
interesting approach to the synthesis of hinckdentine A,4b in
which they attempted to use an intramolecular radical cyclization
to the 12a position of an indolo[1,2-c]quinazoline as the key
step (Scheme 1). A study of the Diels-Alder reaction between
indoles and phenylsulfonylbuta-1,3-dienes has been investigated
with the synthesis of hinckdentine A in mind.5
We planned to synthesize hinckdentine A from a 2-aryl indole
by first preparing the quaternary center of the natural product,
the key structural feature. Intermediate 5 provides a platform
onto which the seven-membered lactam and dihydropyrimidine
rings can be built to form the framework of hinckdentine A as
shown in Scheme 2.
(1) This work was presented in preliminary form: Liu, Y.; McWhorter, W.
W., Jr. Abstracts of Papers, 224th National Meeting of the American
Chemical Society, Boston, MA, August 17-22, 2002, American Chemical
Society, Washington, DC (ORGN 807).
Results and Discussion
The starting material for our synthesis, 2-(2-bromophenyl)-
indole 4, was prepared by the Fischer indole synthesis from
(2) Blackman, A. J.; Hambly, T. W.; Picker, K.; Taylor, W. C.; Thirasasana,
N. Tetrahedron Lett. 1987, 28, 5561.
(3) Kiang, A. K.; Mann, F. G.; Prior, A. F.; Topham, A. J. Chem. Soc. 1956,
1319.
(4) (a) Billimoria, A. D.; Cava, M. P. Heterocycles 1996, 42, 453. (b) Billimoria,
A. D.; Cava, M. P. J. Org. Chem. 1994, 59, 6777.
(5) Barnwell, N.; Beddoes, R. L.; Mitchell, M. B.; Joule, J. A. Heterocycles
1994, 37, 175.
9
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J. AM. CHEM. SOC. 2003, 125, 4240-4252
10.1021/ja021380m CCC: $25.00 © 2003 American Chemical Society

Synthesis of 8-Desbromohinckdentine A
A R T I C L E S
Scheme 3 a
Scheme 4 a
a Reagents and conditions: (a) THF, room temperature, 2 h (89% 14
and 3% 5); (b) 88% HCO2H, toluene, reflux, 30 min (96%).
Scheme 5 a
a
Reagents and conditions: (a) polyphosphoric acid, 120 °C, 4 h (78%);
(b) NaNO2, HOAc, room temperature, 3 h (97%); (c) Na2S2O4, NaOH, H2O,
EtOH, reflux, 24 h (94%); (d) PbO2, benzene, reflux, 24 h (98%); (e) 1 N
HCl (aq), toluene, room temperature, 12 h (42% 12 and 56% 13); (f) reduced
pressure, 105 °C, 4 h (99%).
phenylhydrazine hydrochloride and 2-bromoacetophenone.6 In-
dole 4 can be oxidized to the indolenine 13 in one step using
singlet oxygen,7 but this procedure is not suitable for the
preparation of large amounts of indolenine. We found that the
four-step, high yielding procedure8 shown in Scheme 3 was
suitable for the preparation of 2-(2-bromophenyl)-3H-indol-3-
one 13 in multigram quantities. This procedure8 yields a mixture
of both 12 and 13, but we found that heating this mixture under
vacuum at 105 °C yielded exclusively 13.
We initially anticipated, on the basis of the results of
Marchetti and co-workers,9 that we would be able to add an
allyl anion to indolenine 13 to directly obtain indolone 5, which
contains the quaternary center of hinckdentine A. In fact, when
we added allylmagnesium bromide to indolenine 13, we obtained
indolol 14 (IR OH 3296, 3212 cm-1) containing a trace of
indolone 5 (Scheme 4). Indolol 14 was cleanly converted to
indolone 5 (IR CdO 1675 cm-1) by means of a pinacol-like
rearrangement under acidic conditions.10 There are a few
examples of this type of rearrangement in the literature in which
migration is reported to take place under basic or thermal
conditions.11 This rearrangement is more well known when the
migrating group is tethered to the indole at the 2 position and
has been used to prepare a variety of spirocyclic alkaloids.12
At this point, we considered three possibilities for the
construction of the seven-membered lactam ring.
a Reagents and conditions: (a) Boc2O, DMAP, CH3CN, room temper-
ature, 17 h (96%); (b) O3, MeOH, -78 °C, then Me2S, -78 °C to room
temperature; (c) BnNH2, HOAc, NaBH3CN, MeOH/THF, room temperature,
16 h (71% for b and c); (d) diethylphosphonoacetic acid, HATU, DIEA,
CH2Cl2, 0 °C to room temperature, 24 h (91%); (e) NaH, THF, room
temperature, 17 h.
First, we attempted to form the seven-membered lactam by
means of an intramolecular Horner-Wadsworth-Emmons
reaction (Scheme 5). The secondary amine of indolone 5 was
protected with a Boc group13 to yield 15. The terminal olefin
of 15 was cleaved by ozonolysis to yield the corresponding
aldehyde, which was in turn converted to the benzylamine 16
by a reductive amination. Benzylamine 16 was coupled14 with
diethyl phosphonoacetic acid to yield diethylphosphonate 17.
Our efforts to carry out the intramolecular Horner-Wadsworth-
Emmons reaction using NaH in THF at room temperature for
24 h or LDA in THF at -78 °C followed by warming to room
temperature led only to recovered starting material, while the
(6) Dalton, L.; Humphrey, G. L.; Cooper, M. M.; Joule, J. A. J. Chem. Soc.,
Perkin Trans. 1 1983, 2417.
(12) For examples: (a) Witkop, B.; Patrick, J. B. J. Am. Chem Soc. 1951, 73,
2188. (b) Hutchison, A. J.; Kishi, Y. J. Am. Chem Soc. 1979, 101, 6786.
(c) Williams, R. M.; Glinka, T.; Kwast, E.; Coffman, H.; Stille, J. K. J.
Am Chem. Soc. 1990, 112, 808. (d) Stoermer, D.; Heathcock, C. H. J. Org.
Chem. 1993, 58, 564.
(7) Ling, K.-Q. Synth. Commun. 1995, 25, 3831.
(8) Richman, R. J.; Hassner, A. J. Org. Chem. 1968, 33, 2548.
(9) Berti, C.; Greci, L.; Marchetti, L. J. Chem. Soc., Perkin Trans. 2 1979,
233.
(10) Liu, Y.; McWhorter, W. W. J. Org. Chem. 2003, 68, 2618-2622.
(11) (a) Lednicer, D.; Emmert, D. E. J. Heterocycl. Chem. 1970, 575. (b)
Robinson, B.; Uppal Zubair, M. Pak. J. Sci. Ind. Res. 1976, 19, 214.
(13) Grehn, L.; Gunnarsson, K.; Ragnarsson, U. Acta Chem. Scand. B 1986,
40, 745.
(14) Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397.
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J. AM. CHEM. SOC. VOL. 125, NO. 14, 2003 4241

A R T I C L E S
Liu and McWhorter
Scheme 6 a
Scheme 7 a
a Reagents and conditions: (a) LDA, THF, -78 °C, 5 min; (b) Me3SiCl,
THF, -78 °C to room temperature (78%); (c) silica gel, CH2Cl2/MeOH
(4/1), room temperature, 16 h (25%).
starting material. When indolone 22 was deprotonated kinetically
at -78 °C using LDA in THF,16 we could detect by thin-layer
chromatography (TLC) clean formation of the aldol product 23
without the presence of starting material 22. The reaction is
apparently cleanly quenched on a very small scale on the TLC
plate. Extensive efforts to duplicate this quench on a larger scale
led to the discovery of our best conditions: adding the cold
reaction mixture to a -78 °C solution of 5 equiv of acetic acid
in THF. Under these conditions, we obtained a 54% yield of
the stable aldol product 23 and 39% recovery of 22. This
represents our best result in carrying out this reaction, as the
ratio of aldol 23 to starting material 22 was often lower. We
believe that substantial starting material 22 was recovered upon
protonation of the intermediate alkoxide 23a because protonation
of the carbonyl group of the intermediate, which leads to retro
aldol reaction to yield 22, is competitive with protonation of
the hindered tertiary alkoxide, which leads to aldol 23. Proto-
nation on the carbonyl group followed by reversion to starting
material 22 is also strongly favored entropically as models show
the 2-bromophenyl group to be in a much more sterically
demanding environment in aldol 23 than it occupies in indolone
22. When we attempted to trap the alkoxide intermediate using
trimethylsilyl chloride,17 we observed only the formation of silyl
enol ether 24 (Scheme 7). The silyl enol ether 24 could be
converted to the aldol 23 in low yield by stirring it with silica
gel in a mixture of methanol and CH2Cl2. The relatively clean
detection of aldol 23 on the TLC plate indicates that formation
of aldol 23 can be favored by quenching the intermediate on
the mildly acidic, proton rich silica gel surface, but these
quenching conditions are difficult to reproduce on the scales
necessary for a successful synthesis of hinckdentine A.
a Reagents and conditions: (a) THF, room temperature, 1 h (88%); (b)
88% HCO2H, toluene, reflux, 30 min (89%); (c) Boc2O, DMAP, CH3CN,
room temperature, 17 h (96%); (d) LDA, THF, -78 °C, 5 min; (e) HOAc,
THF, -78 °C to room temperature (54% for d and e).
use of NaH in THF at reflux for 16 h or n-BuLi in THF at -78
°C followed by warming to room temperature led to consump-
tion of 17 without formation of any R,â-unsaturated lactam 18.
It is apparently difficult for this resonance stabilized, bulky
phosphonate anion to attack the sterically hindered ketone.
Although the amine of 17 is acylated with a Boc protecting
group, resonance deactivation of the ketone may also play a
role in the failure of this reaction. We also attempted a similar
ring closure reaction of 19 and found it to be unsuccessful.
Our second plan for the formation of the lactam ring is shown
in Schemes 6 and 8. The Grignard reagent, prepared from
2-methyl-2-(â-bromoethyl)-1,3-dioxolane,15 was added to in-
dolenine 13 to yield 20, which was rearranged and deprotected
under acidic conditions to yield indolone 21. As before, the
amine of 21 was protected with a Boc group13 to yield 22.
Acylation of the amine also enhances the electrophilicity of the
carbonyl of the indolone. We have extensively investigated the
intramolecular aldol condensation of 22 to form 23. All
conditions, which lead to the formation of the thermodynamic
enolate or enol under basic or acidic conditions, yielded a retro-
Michael reaction product with loss of methyl vinyl ketone,
indolone 21, recovered starting material, or destruction of the
The structure of aldol 23 was confirmed by NMR experiments
and subsequent transformations. The HMBC experiment ex-
(15) (a) Ponaras, A. A. Tetrahedron Lett. 1976, 17, 3105. (b) Hsung, R. P. Synth.
Commun. 1990, 20, 1175-1179.
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4242 J. AM. CHEM. SOC. VOL. 125, NO. 14, 2003

Synthesis of 8-Desbromohinckdentine A
A R T I C L E S
Scheme 8 a
Scheme 9 a
a Reagents and conditions: (a) O3, EtOH, -78 °C, 1 h; (b) NaBH4, THF/
EtOH, -78 °C to room temperature (98% for a and b); (c) MsCl, pyridine,
room temperature, 2 h (88%); (d) NaN3, DMF, 100 °C, 12 h (97%); (e) H2,
Pd/C, EtOAc, room temperature, 18 h (99%); (f) Ac2O, pyridine, room
temperature, 20 h (98%); (g) Boc2O, DMAP, CH3CN, room temperature,
17 h (96%); (h) LDA, THF, -78 °C, 5 min, then HOAc, THF, -78 °C to
room temperature.
of the crude product showed the formation of two oxime toluene
p-sulfonates together with a small amount of Beckmann
rearrangement product 28. When crude 27 was warmed in
ethanol at 78 °C, the Beckmann rearrangement product 28 was
obtained in 19% yield. A small amount of one of the oxime
toluene p-sulfonates, literature19 precedent suggests 27b, re-
mained unreacted. Ketone 25 and several byproducts that are
not rearrangement products were detected in this reaction
mixture. The structure assignments of 26a, 26b, and 27a are
based on our assignment of structure 27b to the unrearranged
oxime toluene p-sulfonate and the observation that a sample of
pure 26a was converted into 27a. The acidic conditions
employed by Fleming and Woodward19b to bring about the
Beckmann rearrangement were at best very low yielding and
brought about loss of the Boc protecting group. When a mixture
of 26a and 26b was treated under the conditions of Lyga,19a
Beckmann rearrangement was not observed. Simultaneous to
our investigation of this synthetic sequence, we were investigat-
ing a third approach to the lactam ring which proved to be more
convenient than this route involving the aldol condensation
followed by the Beckmann rearrangement.
a Reagents and conditions: (a) MsCl, pyridine, 0 °C to room temperature,
20 h (76%); (b) HONH3Cl, pyridine, room temperature, 3.5 h (55% 26a
and 45% 26b); (c) TsCl, pyridine, room temperature; (d) EtOH, 78 °C (19%
28 from 25).
hibited a three bond correlation of the quaternary carbon (C.13)
to one of the protons on C.9 and a three bond correlation of
C.7 to the same proton on C.9, indicating that the six-membered
ring had been closed. When the aldol product was treated with
mesyl chloride in pyridine,18 the R,â-unsaturated ketone 25 was
formed (Scheme 8). Ketone 25 was converted to a 6:1 mixture
of oximes 26a and 26b by treatment with hydroxylamine
hydrochloride in ethanol in the presence of pyridine and water.
Treatment of 25 with hydroxylamine hydrochloride in pyridine
resulted in a 55:45 mixture of 26a and 26b. The Beckmann
rearrangement of R,â-unsaturated oximes 26a and 26b is
precedented to yield the desired R,â-unsaturated lactam 28
through the p-toluenesulfonates 27.19 The 55:45 mixture of 26a
and 26b was converted to the corresponding oxime toluene
p-sulfonates 27a and 27b with tosyl chloride in pyridine. This
reaction mixture could not be analyzed by TLC because 27a
and 27b apparently react on the silica gel surface, but the NMR
Our third and most successful effort to prepare the lactam
ring involved direct formation of this ring by means of an aldol
condensation. We initially sought to use the Boc group to protect
the acetamide of 34 during the aldol condensation. Boc protected
amide 34 was prepared from 15 as shown in Scheme 9. The
terminal olefin of 15 was cleaved by ozonolysis, and the
intermediate oxidation products were directly reduced with
20
NaBH4 to yield alcohol 29. Alcohol 29 was converted to
mesylate 30. The mesylate was displaced with azide anion, and
(16) Gaudemar-Bardone, F.; Gaudemar, M. Synthesis 1979, 463.
(17) Palomo, C.; Aizpurua, J. M.; Aurrekoetxea, N.; Lopez, M. C. Tetrahedron
Lett. 1991, 32, 2525.
azide 31 was reduced to amine 32.21 Amine 32 was acylated,
(18) Semeria, D.; Philippe, M.; Delaumeny, J.-M.; Sepulchre, A.-M.; Gero, S.
D. Synthesis 1983, 710.
(20) For an example of this reaction sequence, see: Meyers, A. I.; Reuman,
M.; Gabel, R. A. J. Org. Chem. 1981, 46, 783.
(21) For a recent example of this reaction sequence, see: WO 0224705.
(19) (a) Lyga, J. W. J. Heterocycl. Chem. 1996, 33, 1631. (b) Fleming, I.;
Woodward, R. B. J. Chem. Soc., Perkin Trans. 1 1973, 1653.
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A R T I C L E S
Liu and McWhorter
Scheme 10 a
Scheme 11 a
a Reagents and conditions: (a) Ph2CdNH, t-BuONa, Pd(DPPF)2Cl2,
DPPF, toluene, 140 °C, 48 h (62%); (b) 2 N HCl (aq), THF, room
temperature, 5 h (97%); (c) 20% TFA in CH2Cl2, 0 °C to room temperature,
8 h (95%); (d) 1:1 HCO2H (96%)/2-propanol, 75 °C, 4 h (72%); (e) HCO2H
(96%), 100 °C, 2 h (93%).
a Reagents and conditions: (a) O3, MeOH, -78 °C, then Me2S, -78 °C
to room temperature; (b) 2,4-dimethoxybenzylamine, HOAc, NaBH3CN,
MeOH/THF, room temperature, 16 h (60% for a and b); (c) Ac2O, pyridine,
0 °C to room temperature, 20 h (91%); (d) LDA, THF, -78 °C, 5 min,
then HOAc, THF, -78 °C to room temperature (92%); (e) MsCl, pyridine,
0 °C to room temperature, 20 h (96%); (f) Mg turnings, MeOH, room
temperature, 24 h (79%).
powerful because the bromine of 40 is in a very sterically
congested environment due to the enormous orthosubstituent
on the aromatic ring. It should be noted that we required a higher
reaction temperature (140 °C) than is reported in the litera-
ture25,26 to successfully bring about this transformation. We
examined a number of aromatic amination conditions and
catalysts before finding the ones that gave a successful result.
The diphenylmethylidene protecting group of 41 is cleaved using
2 N aqueous HCl in THF26 to yield 42, and the Boc protecting
group was cleaved using trifluoroacetic acid in CH2Cl2 to give
aniline 43. Condensation of 43 with formic acid in 1:1 formic
acid/2-propanol at 75 °C resulted in formation of the pyrimidine
ring containing 44. When the condensation was attempted in
formic acid at 100 °C,3 the dimethoxybenzyl protecting group
was removed prior to complete formation of the pyrimidine ring,
and the resulting unprotected diamine displayed poor solubility
in formic acid such that the formation of the pyrimidine ring
proceeded sluggishly in low yield. The dimethoxybenzyl
protecting group was cleaved from 44 in formic acid at 100 °C
to yield the framework of hinckdentine A 6.27 The observed
coupling constants between the hydrogens of C.12 and C.11b
(J ) 6.3 and 3.1 Hz) are very nearly identical to those observed
with hinckdentine A (J ) 6.2 and 3.0 Hz)1 and indicate that
first to yield 33, and a second time to yield 34. Although there
is good literature precedent,22 we were unsuccessful in bringing
about the formation of aldol 35. Amide 34 was consumed, but
cyclization products could not be detected.
As a result, we decided to replace the Boc protecting group
of 34 with a benzyl protecting group (Scheme 10). We chose
the 2,4-dimethoxybenzyl protecting group23 because it can be
more readily removed under milder conditions from a lactam
than an unsubstituted benzyl protecting group. As before, the
terminal olefin of 15 was cleaved by ozonolysis, and the
resulting aldehyde was converted to benzylamine 36. Amine
36 was acetylated under standard conditions to yield 37.
Deprotonation of acetamide 37 at -78 °C with LDA16 followed
by quenching with acetic acid in THF at -78 °C resulted in
formation of aldol 38 in 92% yield. Aldol 38 was treated with
mesyl chloride in pyridine18 to yield the R,â-unsaturated amide
39, which was in turn reduced to lactam 40 using magnesium
in methanol.24
The framework of hinckdentine A 6 is constructed from 40
as shown in Scheme 11. Palladium-catalyzed amination of 40
using benzophenone imine yielded 41 in 62% yield.25 The
conditions used to bring about amination of 40 are extremely
(22) For examples, see: (a) Rassu, G.; Auzzas, L.; Pinna, L.; Battistini, L.;
Zanardi, F.; Marzocchi, L.; Acquotti, D.; Casiraghi, G. J. Org. Chem. 2000,
65, 6307. (b) Rassu, G.; Auzzas, L.; Pinna, L.; Zanardi, F.; Marzocchi, L.;
Casiraghi, G. Org. Lett. 1999, 1, 1213.
(23) Madar, D. J.; Kopecka, H.; Pireh, D.; Pease, J.; Pliushchev, M.; Sciotti, R.
J.; Wiedeman, P. E.; Djuric, S. W. Tetrahedron Lett. 2001, 42, 3681.
(24) (a) Brettle, R.; Shibib, S. M. Tetrahedron Lett. 1980, 21, 2915. (b) Brettle,
R.; Shibib, S. M. J. Chem. Soc., Perkin Trans. 1 1981, 2912.
(25) Mann, G.; Hartwig, J. F.; Driver, M. S.; Fernandez-Rivas, C. J. Am. Chem.
Soc. 1998, 120, 827.
(26) Wolfe, J. P.; Ahman, J.; Sadighi, J. P.; Singer, R. A.; Buchwald, S. L.
Tetrahedron Lett. 1997, 38, 6367.
(27) The reaction sequences shown in Schemes 10 and 11 were first carried out
with a benzyl protecting group instead of a 2,4-dimethoxybenzyl protecting
group, but despite extensive experimentation, conditions could not be found
which allowed the benzyl group to be removed to yield 6.
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4244 J. AM. CHEM. SOC. VOL. 125, NO. 14, 2003

Synthesis of 8-Desbromohinckdentine A
A R T I C L E S
Figure 2. Crystal structure of 8-desbromohinckdentine A.
Figure 1. Crystal structure of the hinckdentine framework.
Further bromination of 45 required much harsher reaction
conditions. We found that tribrominated products were formed
when a mixture of 98% sulfuric acid and fuming sulfuric acid
(1:1) was used as the solvent,32 but this harsh reaction condition
resulted in the formation of other side products. Bromination
of 45 with 1,3-dibromo-5,5-dimethylhydantoin/CF3SO3H in
Scheme 12 a
33
CH2Cl2 at room temperature resulted in a mixture of tribro-
minated and tetrabrominated as well as more highly brominated
products, all of which were isomeric mixtures. Hinckdentine A
1 may have been present in this mixture, but we were unable
to chromatographically separate all of the isomeric bromides.
The formation of many tribromination products with little
selectivity after the clean formation of dibrominated 45 surprised
us. We had expected primarily products derived from the
bromination of positions 4 and 8.
a
Reagents and conditions: (a) Br2, HCO2H, room temperature, 48 h
(92%).
the magnesium in methanol reduction has fixed the correct
relative stereochemistry between the quaternary center and
C.11b. Crystalline 6 was submitted to X-ray analysis, and the
results (Figure 1) clearly show that the stereochemical relation-
ships of 6 correspond to those of hinckdentine A 1.
Conclusion
We have produced the first synthesis of the hinckdentine A
framework 6 using a 19 step reaction sequence from readily
available starting materials. We first formed the quaternary
center of hinckdentine A using an uncommon pinacol-like
rearrangement of an indolol 14 to yield key intermediate 5. The
lactam was built onto this intermediate using a reaction sequence
that featured an efficient seven-membered ring-forming in-
tramolecular aldol condensation as the key step. The R,â-
unsaturated lactam 39 was reduced to the corresponding
saturated lactam 40 with complete stereocontrol. The dihydro-
pyrimidine ring was prepared by means of a reaction sequence
in which the remarkable palladium-catalyzed amination of
arylbromide 40 is the key step. This reaction sequence also
includes the clean condensation of formic acid with diamine
43 to yield the framework of the natural product. With the
framework of hinckdentine A 6 in hand, we investigated the
bromination of this structure and found that we could efficiently
introduce bromine at the 2 and 10 positions to yield 8-desbro-
mohinckdentine A.
Although we had originally planned to modify our synthesis
of the hinckdentine A framework to allow introduction of
bromine at an earlier stage, with a successful synthesis of the
hinckdentine framework 6 realized, we decided to study the
direct bromination of this structure. One can argue on the basis
of known brominations of 3,4-dihydroquinazolines28 and indo-
lines29 that it is possible to brominate the dihydroindolo[1,2-
c]quinazoline ring system of 6 at the 2, 8, and 10 positions.
Biosynthetically, bromine is probably introduced at a late stage
of the biosynthesis of hinckdentine A.30 Bromination of 6 with
bromine in ethanol or chloroform at 60 °C resulted in the
sluggish formation of a mixture of monobrominated and
dibrominated products. A trace amount of tribrominated products
could be detected by LC-MS. Bromination in 96% formic acid
(Scheme 12),31 methanesulfonic acid, or trifluoromethane-
sulfonic acid at room temperature for 48 h furnished cleanly a
single dibrominated product 45 whose structure was elucidated
with 1H NMR, 1H-1H COSY NMR, and X-ray crystallography
(Figure 2). This bromination reaction can be accelerated by the
addition of iodine and iron powder or by heating at 60 °C.
Experimental Section
General. Proton and 13C magnetic resonance spectra were recorded
on a 400 MHz/100 Hz Bruker spectrometer and are reported in ppm
on the δ scale. Infrared spectra (IR), ultraviolet spectra (UV), high-
resolution mass spectra (HRMS), and combustion analyses were
(28) Telezhenetskaya, M. V.; D’yakonov, A. L. Khim. Prir. Soedin. 1987, 309.
(29) Kiguchi, T.; Kuninobu, N.; Takahashi, Y.; Yoshida, Y.; Naito, T.; Ninomiya,
I. Synthesis 1989, 778.
(30) Vanadium bromoperoxidase is believed to be responsible for the bromination
of many marine natural products, see: Martinez, J. S.; Carroll, G. L.;
Tschirret-Guth, R. A.; Altenhoff, G.; Little, R. D.; Butler, A. J. Am. Chem.
Soc. 2001, 123, 3289.
(32) Harada, K.; Hart, H.; Du, C. F. J. Org. Chem. 1985, 50, 5524.
(33) Euguchi, H.; Kawaguchi, H.; Yoshinaga, S.; Nishida, A.; Nishiguchi, T.;
Fujisaki, S. Bull. Chem. Soc. Jpn. 1994, 67, 1918.
(31) Toropin, N. V.; Burmistrov, K. S.; Burmistrov, S. I.; Zaichenko, N. L. Zh.
Org. Khim. 1986, 22, 999-1005.
9
J. AM. CHEM. SOC. VOL. 125, NO. 14, 2003 4245

A R T I C L E S
Liu and McWhorter
determined by the Analytical Chemistry Department of Pharmacia.
Anhydrous THF was distilled prior to use from sodium metal/
benzophenone. Acetonitrile and methanol were dried over 3A/4A
molecular sieves. Diisopropylamine and N,N-diisopropylethylamine
were distilled from calcium hydride prior to use. Pyridine was dried
by reflux and distillation over KOH. Toluene was distilled from sodium
metal prior to use. Anhydrous benzene was purchased from Aldrich in
Sure-Seal bottles. All other commercially available solvents and reagents
were used without further purification. All moisture-sensitive reactions
were conducted under N2. Brine refers to a saturated aqueous sodium
chloride solution. Solvent removal was accomplished by a rotary
evaporator operating at house vacuum (40-50 Torr). Column chro-
matography was performed with silica gel 60 (EM Science, 230-400
mesh ASTM).
2-(2-Bromophenyl)indole (4). 2-Bromoacetophenone (50.0 g, 251.19
mmol) and phenylhydrazine hydrochloride (54.5 g, 376.90 mmol) were
mixed with polyphosphoric acid (780 g), and the mixture was heated
with stirring. The temperature of the reaction mixture was kept at 100-
110 °C for 4 h. It was poured into ice water (2.4 L) and extracted with
EtOAc (8 × 200 mL). The combined extracts were dried over Na2-
SO4. The dried extracts were concentrated, and the crude product was
chromatographed (SiO2, 10:1 hexane/EtOAc to yield 4 (53.3 g, 78%).
1H NMR (CDCl3): δ 6.85 (dd, J ) 2.1 and 0.8 Hz, 1H), 7.17 (ddd, J
) 7.5, 7.0, and 1.0 Hz, 1H), 7.22-7.28 (2H), 7.42 (ddd, J ) 7.6, 7.5,
and 1.3 Hz, 1H), 7.46 (dd, J ) 8.1 and 0.8 Hz, 1H), 7.64 (dd, J ) 7.9
and 1.7 Hz, 1H), 7.68-7.73 (2H), 8.68 (br s, 1H, NH); ESI-MS m/z
272 (MH+). Anal. Calcd for C14H10BrN: C, 61.79; H, 3.70; N, 5.15.
Found: C, 61.48; H, 3.52; N, 5.16.
hexane/EtOAc) to afford 12 (11.42 g, 42%) and 13 (14.33 g, 56%).
12, 1H NMR (CDCl3): δ 7.34-7.41 (2H), 7.47 (ddd, J ) 7.6, 7.5, and
1.3 Hz, 1H), 7.53 (d, J ) 7.5 Hz, 1H), 7.59-7.65 (3H), 7.74 (dd, J )
7.9 and 1.3 Hz, 1H); HRMS calcd C14H11BrNO2 (MH+) 302.9895,
found 287.9895. 13, 1H NMR (CDCl3): δ 7.34-7.41 (2H), 7.47 (ddd,
J ) 7.6, 7.5, and 1.3 Hz, 1H), 7.53 (d, J ) 7.5 Hz, 1H), 7.59-7.65
(3H), 7.74 (dd, J ) 8.1 and 1.0 Hz, 1H); HRMS calcd C14H9BrNO
(MH+) 285.9868, found 285.9877. Anal. Calcd for C14H8BrNO: C,
58.77; H, 2.82; N, 4.90. Found: C, 58.71; H, 2.82; N, 4.86.
Dehydration of 12 to 13. Compound 12 (11 g, 36.17 mmol) was
placed in a flask and heated in a 110 °C oil bath under reduced pressure
for 4 h to furnish 13 (10.25 g, 99%).
3-Allyl-2-phenyl-3H-indol-3-ol (14). Indolone 13 (8.58 g, 30 mmol)
was dissolved in dry THF (600 mL). At room temperature, a solution
of allylmagnesium bromide in ethyl ether/THF (0.10 M, 330 mL, 33
mmol, made by dilution of 1.0 M ethyl ether solution with THF) was
added in a slow dropwise fashion. After being stirred for 2 h, the
reaction mixture was concentrated to a small volume, diluted with
EtOAc (400 mL), and washed with 10% aqueous NH4Cl solution (300
mL). The aqueous wash was extracted with EtOAc (4 × 80 mL). The
combined EtOAc extracts were washed with brine (80 mL), dried over
Na2SO4, filtered, and concentrated. The crude product was chromato-
graphed (SiO2, hexane/EtOAc) to afford product 14 (8.76 g, 89%)
together with a minor amount of 5 (295 mg, 3%). 14, IR: 3296 (br),
3212 (br), 3072, 3009, 2977, 2926, 2905, 1638, 1617, 1589, 1569, 1467,
916, 908, 902 cm-1. 1H NMR (CDCl3): δ 2.53 (s, 1H, OH), 2.53 (dd,
J ) 14.0 and 7.9 Hz, 1H), 2.75 (dd, J ) 14.0 and 6.8 Hz, 1H), 5.09
(dd, J ) 17.0 and 1.5 Hz, 1H), 5.14 (dd, J ) 10.2 and 1.5 Hz, 1H),
5.67 (dddd, J ) 17.0, 10.2, 7.9, and 6.8 Hz, 1H), 7.30-7.36 (2H),
7.41-7.47 (3H), 7.66 (d, J ) 7.7 Hz, 1H), 7.74 (dd, J ) 8.0 and 1.1
Hz, 1H), 7.78 (dd, J ) 7.7 and 1.7 Hz, 1H); HRMS calcd C17H15-
BrNO (MH+) 328.0337, found 328.0329. Anal. Calcd for C17H14-
BrNO: C, 62.21; H, 4.30; N, 4.27. Found: C, 62.27; H, 4.28; N, 4.28.
2-Allyl-2-(2-bromophenyl)-1,2-dihydro-3H-indol-3-one (5). To a
solution of 14 (8.53 g, 26 mmol) in toluene (100 mL) was added 88%
aqueous formic acid (20 mL). After being stirred and refluxed for 30
min, the reaction mixture was cooled to room temperature and carefully
poured into a saturated Na2CO3 solution (300 mL). The organic layer
was separated, and the aqueous layer was extracted with EtOAc (4 ×
80 mL). The combined organic solution layers were washed with brine
(30 mL), dried over Na2SO4, and concentrated. The crude product was
chromatographed (SiO2, 10:1 hexane/EtOAc) to afford 5 (8.19 g, 96%).
IR: 3345, 3301, 3076, 3058, 3006, 2979, 2903, 1675, 1618, 1586, 1490,
2-(2-Bromophenyl)-3-nitrosoindole (9). To a magnetically stirred
solution of 4 (48.0 g, 176.37 mmol) in acetic acid (1000 mL) was added
sodium nitrite (30 g, 434.78 mmol) slowly and portionwise during 2.5
h. The reaction mixture was stirred for an additional 30 min and then
poured into 2.5 L of water. The precipitate was collected by filtration
and dried under reduced pressure to afford a yellow solid 5 (51.5 g,
1
97%). H NMR (CD3OD): δ 7.39-7.45 (3H), 7.48-7.57 (3H), 7.75
(dd, J ) 8.1 and 1.0 Hz, 1H), 8.18 (d, J ) 7.3 Hz, 1H); HRMS calcd
for C14H10BrN2O (MH+) 300.9977, found 300.9966. Anal. Calcd for
C14H9BrN2O: C, 55.84; H, 3.01; N, 9.30. Found: C, 55.26; H, 2.99;
N, 9.19.
3-Amino-2-(2-bromophenyl)indole (10). To a solution of 9 (36.0
g, 119.54 mmol) in ethanol (250 mL) were added sodium hydrosulfite
(30 g, 172.30 mmol) and 2 N NaOH solution (250 mL). The reaction
mixture was heated to reflux. An additional 30 g (172.30 mmol) of
sodium hydrosulfite was added portionwise during 24 h. The reaction
mixture was cooled to room temperature, and the solids were collected
by filtration. The solids were washed with water (4 × 25 mL) and
1
1467, 1330, 1318, 1301, 1286, 1272, 935, 928, 910 cm-1. H NMR
(CDCl3): δ 2.90 (dd, J ) 14.0 and 7.1 Hz, 1H), 3.30 (dd, J ) 14.0
and 7.3 Hz, 1H), 5.03 (d, J ) 10.0 Hz, 1H), 5.18 (dd, J ) 17.0 and 1.3
Hz, 1H), 5.37 (dddd, J ) 17.0, 10.0, 7.3, and 7.1 Hz, 1H), 5.95 (br,
1H, NH), 6.84 (dd, J ) 7.7 and 7.3 Hz, 1H), 6.88 (d, J ) 8.3 Hz, 1H),
7.17 (ddd, J ) 7.8, 7.5, and 1.5 Hz, 1H), 7.31 (ddd, J ) 7.9, 7.3, and
1.2 Hz, 1H), 7.47 (ddd, J ) 8.3, 7.0, and 1.3 Hz, 1H), 7.64-7.69 (3H).
13C NMR (CDCl3): δ 41.9, 72.1, 112.6, 119.3, 120.0, 121.4, 123.2,
125.0, 127.9, 129.7, 129.7, 131.9, 135.6, 137.7, 138.0, 160.3, 201.6.
HRMS calcd C17H15BrNO (MH+) 328.0337, found 328.0340. Anal.
Calcd for C17H14BrNO: C, 62.21; H, 4.30; N, 4.27. Found: C, 62.17;
H, 4.30; N, 4.08.
1
dried under reduced pressure for 14 h to yield 10 (32.26 g, 94%). H
NMR (CDCl3): δ 7.15 (ddd, J ) 7.5, 7.1, and 1.0 Hz, 1H), 7.22-7.28
(2H), 7.36 (d, J ) 8.1 Hz, 1H), 7.41 (ddd, J ) 7.6, 7.5, and 1.3 Hz,
1H), 7.59-7.63 (2H), 7.73 (dd, J ) 8.1 and 1.0 Hz, 1H), 7.82 (br s,
1H, NH); HRMS calcd C14H12BrN2 (MH+) 287.0184, found 287.0178.
2-(2-Bromophenyl)-3-imino-indole (11). To a solution of 10 (25.6
g, 89.15 mmol) in benzene was added lead(IV) oxide (86 g, 359.55
mmol). After being refluxed for 24 h, the reaction mixture was filtered,
and the filtrate was concentrated. Chromatography of the concentrated
crude product (SiO2, 3:1 hexane/EtOAc) afforded 11 (24.91 g, 98%).
1H NMR (CDCl3): δ 7.36-7.62 (7H), 7.76 (d, J ) 7.9 Hz, 1H); HRMS
calcd C14H10BrN2 (MH+) 285.0028, found 285.0014.
2-(2-Bromophenyl)-2-hydroxy-1,2-dihydro-3H-indol-3-one (12)
and 2-(2-Bromophenyl)-3H-indol-3-one (13). To a solution of 11 (25.5
g, 89.43 mmol) in toluene (250 mL) was added a 2 N HCl aqueous
solution (250 mL). After being stirred for 12 h, the reaction mixture
was diluted with EtOAc (400 mL) and washed with water (400 mL).
The aqueous phase was extracted with EtOAc (6 × 150 mL), and the
combined organic phases were washed with brine, dried over Na2SO4,
and concentrated. The crude product was chromatographed (SiO2, 9:2
tert-Butyl 2-Allyl-2-(2-bromophenyl)-3-oxoindoline-1-carboxylate
(15). To a magnetically stirred solution of 5 (5.64 g, 17.18 mmol) and
4-(dimethylamino)pyridine (8.4 g, 68.75 mmol) in acetonitrile (300 mL)
was added a solution of di(tert-butyl) dicarbonate (12.39 g, 56.76 mmol)
in acetonitrile (100 mL). After being stirred for 17 h under N2, the
reaction mixture was concentrated under reduced pressure, and the
residue was partitioned between EtOAc (300 mL) and saturated NH4-
Cl solution (300 mL). The aqueous phase was extracted with EtOAc
(3 × 100 mL). The combined extracts were washed with saturated
NaHCO3 solution, dried over Na2SO4, and concentrated. The crude
product was chromatographed (SiO2, 10:1 hexane:EtOAc) to afford 15
9
4246 J. AM. CHEM. SOC. VOL. 125, NO. 14, 2003

Synthesis of 8-Desbromohinckdentine A
A R T I C L E S
(7.07 g, 96%). IR: 3073, 3004, 2977, 2927, 1710, 1607, 1465, 1392,
1360, 1277, 1254, 1157, 1143, 1009, 997, 920, 760, 748 cm-1. 1H NMR
(CDCl3): δ 1.26 (s, 9H), 3.18 (dd, J ) 12.7 and 6.6 Hz, 1H), 3.46 (br
m, 1H), 4.95 (dd, J ) 10.0 and 1.9 Hz, 1H), 5.13 (dd, J ) 17.0 and
1.9 Hz, 1H), 5.43 (dddd, J ) 16.8, 10.1, 7.9, and 6.6 Hz, 1H), 7.15-
7.22 (2H), 7.41 (ddd, 8.1, 7.8, and 1.3 Hz, 1H), 7.54 (dd, J ) 7.8 and
1.3 Hz, 1H), 7.65-7.70 (2H), 7.74 (d, J ) 7.7 Hz, 1H), 8.31 (broad s,
1H); HRMS calcd C22H23BrNO3 (MH+) 428.0862, found 428.0859.
Anal. Calcd for C22H22BrNO3: C, 61.69; H, 5.18; N, 3.27. Found: C,
61.85; H, 5.28; N, 3.33.
2-(2-Bromophenyl)-3-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-3H-in-
dol-3-ol (20). To a solution of indolone 13 (6 g, 20.97 mmol) in dry
THF (900 mL) stirred magnetically at room temperature under N2 was
added dropwise a solution of 3,3-ethylenedioxylbutylmagnesium
bromide (∼1.0 M, 25-30 mL) that was freshly prepared according to
the literature15 procedure. Complete consumption of starting material
was confirmed by thin-layer chromatography (2:1 hexane/EtOAc). After
being stirred for 1 h, the reaction mixture was concentrated under
reduced pressure, then diluted with EtOAc (200 mL) and washed with
10% NH4Cl solution (200 mL). The aqueous wash was extracted with
EtOAc (4 × 50 mL). The combined EtOAc solutions were washed
with brine, dried over Na2SO4, and concentrated. The residual crude
product was purified by chromatography (SiO2, 4:1 hexane/EtOAc) to
tert-Butyl 2-[2-(Benzylamino)ethyl]-2-(2-bromophenyl)-3-oxoin-
doline-1-carboxylate (16). Olefin 15 (1.52 g, 3.54 mmol) was dissolved
in methanol (40 mL) and cooled to -78 °C under N2. O3, from an
ozone generator, was bubbled through the reaction mixture until a faint
blue color appeared in the reaction mixture. Complete consumption of
starting material was confirmed by thin-layer chromatography (4:1
hexane/EtOAc). After the mixture was bubbled with N2 for 15 min,
methyl sulfide (2.5 mL, 34 mmol) was added, and the reaction mixture
was allowed to warm to room temperature during 1.5 h. This solution
was concentrated and diluted with a mixed solvent of 1:1 MeOH/THF
(60 mL), and the resulting solution was cooled to 0 °C. Benzylamine
(1.90 g, 17.7 mmol) followed by acetic acid (2.23 mL, 39 mmol) was
added to the reaction mixture which was stirred at 0 °C for 30 min.
NaCNBH3 (460 mg, 7.32 mmol) was added, and the reaction mixture
was allowed to warm to room temperature and was stirred at room
temperature for 6 h. Another portion of NaCNBH3 (220 mg, 3.5 mol)
was added, and the reaction mixture was stirred for an additional 10 h.
The reaction mixture was concentrated and diluted with water (100
mL) and extracted with EtOAc (4 × 50 mL). The combined extracts
were washed with saturated Na2CO3 solution, dried over Na2SO4, and
concentrated. The crude product was purified by chromatography (SiO2,
6:5 hexane/EtOAc) to afford 16 (1.32 g, 71%). IR: 3335, 3079, 3062,
3026, 3000, 2975, 2931, 2871, 2852, 1712, 1605, 1591, 1495, 1473,
1466, 1393, 1366, 1265, 1252, 1164, 771, 755, 747, 699 cm-1. 1H NMR
(CD3OD): δ 1.23 (s, 9H), 2.41 (ddd, J ) 11.7, 11.4, and 4.6 Hz, 1H),
2.56 (ddd, J ) 11.7, 11.4, and 4.6 Hz, 1H), 2.68 (ddd, J ) 11.7, 11.4,
and 4.6 Hz, 1H), 2.98 (ddd, J ) 11.7, 11.4, and 4.6 Hz, 1H), 3.72 (s,
2H), 7.22-7.33 (7H), 7.48 (ddd, J ) 7.8, 6.7, and 1.3 Hz, 1H), 7.57
(dd, J ) 7.8 and 1.3 Hz, 1H), 7.70 (d, J ) 7.7 Hz, 1H), 7.75-7.81
(2H), 8.26 (broad s, 1H); HRMS calcd C28H30BrN2O3 (MH+) 521.1440,
found 521.1433. Anal. Calcd for C28H29BrN2O3: C, 64.49; H, 5.61;
N, 5.37. Found: C, 64.62; H, 5.58; N, 5.00.
1
furnish 20 (8.41 g, 88%). H NMR (CDCl3): δ 1.24 (s, 3H), 1.52-
1.67 (2H), 1.96 (ddd, J ) 13.8, 10.3, and 5.4 Hz, 1H), 2.10 (ddd, J )
13.7, 10.4, and 5.9 Hz, 1H), 3.08 (br s, 1H, OH), 3.78-3.93 (4H),
7.30-7.35 (2H), 7.41-7.47 (3H), 7.64 (d, J ) 7.5 Hz, 1H), 7.74 (dd,
J ) 8.1 and 1.2 Hz, 1H), 7.84 (d, J ) 7.7 and 1.7 Hz, 1H); HRMS
calcd C20H21BrNO3 (MH+) 402.0705, found 402.0697.
2-(2-Bromophenyl)-2-(3-oxobutyl)-1,2-dihydro-3H-indol-3-one (21).
To a solution of 20 (8.33 g, 20.7 mmol) in toluene (200 mL) was added
88% formic acid (40 mL), and the reaction mixture was refluxed for
30 min. After being cooled to room temperature, the reaction mixture
was poured into saturated Na2CO3 solution (400 mL) slowly and
carefully and extracted with EtOAc (4 × 100 mL). The combined
extracts were washed with brine (50 mL), dried over Na2SO4, and
concentrated. Chromatographic purification of the crude product (SiO2,
4:1 hexane/EtOAc) afforded 21 (6.60 g, 89%). IR: 3363, 3064, 3023,
1
2933, 1710, 1694, 1646, 1615, 1567, 1487, 1468, 754, 733 cm-1. H
NMR (CDCl3): δ 2.06 (s, 3H), 2.24 (m, 1H), 2.42-2.57 (2H), 2.82
(m, 1H), 6.10 (br s, 1H, NH), 6.83-6.89 (2H), 7.17 (ddd, J ) 7.9, 7.5,
and 1.7 Hz, 1H), 7.30 (ddd, J ) 8.4, 7.3, and 1.5 Hz, 1H), 7.50 (ddd,
J ) 7.7, 7.1, and 1.5 Hz, 1H), 7.61 (dd, J ) 7.9 and 1.7 Hz, 1H), 7.65
(dd, J ) 7.9 and 1.2 Hz, 1H), 7.70 (d, J ) 7.7 Hz, 1H); HRMS calcd
C18H17BrNO2 (MH+) 358.0443, found 358.0443. Anal. Calcd for C18H16-
BrNO2: C, 60.35; H, 4.50; N, 3.91. Found: C, 60.71; H, 4.51; N, 3.92.
tert-Butyl 2-(2-Bromophenyl)-3-oxo-2-(3-oxobutyl)indoline-1-car-
boxylate (22). To a magnetically stirred solution of 21 (5.64 g, 15.8
mmol) and 4-(dimethylamino)pyridine (8.4 g, 68.75 mmol) in aceto-
nitrile (300 mL) was added a solution of di-tert-butyl dicarbonate (12.39
g, 56.76 mmol) in acetonitrile (100 mL). After being stirred for 17 h
under N2, the reaction mixture was concentrated under reduced pressure,
and the residue was partitioned between EtOAc (300 mL) and saturated
NH4Cl solution (300 mL). The aqueous phase was extracted with EtOAc
(3 × 100 mL). The combined extracts were washed with saturated
NaHCO3 solution, dried over Na2SO4, and concentrated. The crude
product was chromatographed (SiO2, 9:2 hexane/EtOAc) to afford 22
(6.93 g, 96%). IR: 3006, 2985, 2971, 2933, 1709, 1604, 1592, 1461,
tert-Butyl 2-(2-{Benzyl[(diethoxyphosphoryl)acetyl]amino}ethyl)-
2-(2- bromophenyl)-3-oxoindoline-1-carboxylate (17). To a solution
of 16 (260 mg, 0.5 mmol), diethylphosphonoacetic acid (98 mg, 0.5
mmol), and N,N-diisopropylethylamine (129.3 mg, 1.0 mmol) in
methylene chloride (20 mL) was added HATU (190 mg, 0.5 mmol).
After being stirred at room temperature for 24 h, the reaction mixture
was concentrated under reduced pressure and then diluted with EtOAc
(50 mL). The EtOAc solution was washed with saturated NH4Cl
solution (30 mL). The aqueous wash was extracted with EtOAc (3 ×
10 mL), and the combined EtOAc layers were washed with brine (10
mL), dried over Na2SO4, filtered, and concentrated to furnish the crude
product which was purified by chromatography (SiO2, 1.5:9.5 hexane/
EtOAc) to afford 17 (318 mg, 91%). IR: 3075, 3055, 2980, 2932, 1712,
1676, 1605, 1591, 1554, 1474, 1466, 1394, 1361, 1251, 1202, 1163,
1054, 1026, 972, 769, 757 cm-1. 1H NMR (CDCl3) δ 1.21-1.26 (12H),
1.35 (dt, J ) 7.0 and 2.8 Hz, 3H), 2.66 (m, 0.5H), 2.74 (m, 0.5H),
2.78 (m, 0.5H), 2.92-3.06 (3.5H), 3.19 (m, 0.5H), 3.58 (m, 0.5H),
4.10-4.24 (4H), 4.54 (d, J ) 17.2 Hz, 0.5H), 4.58 (s, 1H), 4.70 (d, J
) 17.2 Hz, 0.5H), 7.10-7.34 (7H), 7.40 (m, 1H), 7.51 (dd, J ) 8.2
and 8.1 Hz, 1H), 7.58 (d, J ) 7.1 Hz, 0.5H), 7.67 (dd, J ) 8.4 and 7.3
Hz, 1H), 7.72 (dd, J ) 8.2 and 7.7 Hz, 1H), 7.81 (d, J ) 6.9 Hz,
0.5H), 8.17-8.23 (1H); HRMS calcd C34H41BrN2O7P (MH+) 699.1835,
found 699.1841. Anal. Calcd for C34H40BrN2O7P: C, 58.37; H, 5.76;
N, 4.00. Found: C, 58.05; H, 5.91; N, 3.93.
1
1273, 1167, 1160, 762, 754 cm-1. H NMR (CDCl3): δ 1.24 (s, 9H),
2.03 (s, 3H), 2.24-2.32 (2H), 2.74 (m, 1H), 2.97 (m, 1H), 7.18-7.25
(2H), 7.42 (dd, J ) 7.3 and 6.7 Hz, 1H), 7.53 (dd, J ) 7.9 and 1.5 Hz,
1H), 7.70-7.78 (3H), 8.33 (br s, 1H); HRMS calcd C23H25BrNO4
(MH+) 458.0967, found 458.0971. Anal. Calcd for C23H24BrNO4: C,
60.27; H, 5.28; N, 3.06. Found: C, 60.39; H, 5.36; N, 3.02.
tert-Butyl 9a-(2-Bromophenyl)-4a-hydroxy-3-oxo-1,2,3,4,4a,9a-
hexahydro-9H-carbazole-9-carboxylate (23). A solution of dry di-
isopropylamine (536 mg, 5.03 mmol) in dry THF (50 mL) was cooled
to -78 °C, and a solution of butyllithium in hexane (1.6 M, 3.06 mL,
4.9 mol) was added. After being stirred for 10 min at -78 °C under
N2, a solution of 22 (1.87 g, 4.08 mmol) in THF (40 mL) that had
been cooled to -78 °C was added to the lithium diisopropylamide/
THF solution. After the complete consumption of starting material,
which was confirmed by thin-layer chromatography (2:1 hexane/
EtOAc), the reaction mixture was poured into a solution of acetic acid
(1.17 mL, 20.4 mmol) in THF (90 mL) at -78 °C. The resulting mixture
was partitioned between water (200 mL) and EtOAc (200 mL), and
9
J. AM. CHEM. SOC. VOL. 125, NO. 14, 2003 4247

A R T I C L E S
Liu and McWhorter
the aqueous layer was neutralized with saturated Na2CO3 solution and
extracted with EtOAc (3 × 50 mL). The combined extracts were washed
with brine (50 mL), dried over Na2SO4, and concentrated. The crude
product was purified by chromatography (SiO2, 8.7:2.3 hexane/EtOAc)
to afford 23 (1.01 g, 54%) and recovered 22 (729 mg, 39%). IR: 3551,
3441, 3065, 2974, 2929, 1705, 1603, 1482, 1464, 1392, 1372, 1315,
(2H); HRMS calcd C23H23BrNO3 (MH+) 440.0862, found 440.0863.
Anal. Calcd for C23H22BrNO3: C, 62.74; H, 5.04; N, 3.18. Found: C,
61.60; H, 5.05; N, 3.06.
tert-Butyl 9a-(2-Bromophenyl)-3-(hydroxyimino)-1,2,3,9a-tet-
rahydro-9H-carbazole-9-carboxylate (26). A suspension of 25 (400
mg, 0.908 mmol) in EtOH (20 mL) was heated at 50 °C until a complete
solution was obtained. Pyridine (2 mL) and aqueous hydroxylamine
solution (4.0 M, 273 µL, 1.09 mmol) were added sequentially, and the
reaction mixture was refluxed for 30 min. After being cooled to room
temperature, the reaction mixture was poured into ice-cold water (150
mL) and extracted with EtOAc (4 × 50 mL). The combined extracts
were washed with brine (20 mL), dried over Na2SO4, and concentrated.
The crude product was chromatographed with (SiO2, 3.4:1 hexane/
EtOAc) to afford 26a (322 mg, 78%) and 26b (53.8 mg, 13%). 26b is
more polar than 26a. 26b rapidly equilibrates at room temperature to
1
1290, 1249, 1163, 1105, 1083, 1065, 1024, 759, 731 cm-1. H NMR
(CD3OD) δ 1.14 (s, 9H), 1.33-1.68 (br s, 1H), 1.94 (ddd, J ) 18.5,
14.7, and 3.1 Hz, 1H), 2.36 (br d, J ) 19.3 Hz, 1H), 2.80 (d, J ) 15.1
Hz, 1H), 2.85 (br s, 1H), 3.28 (br s, 1H), 7.06 (dd, J ) 7.5 and 7.5 Hz,
1H), 7.17 (dd, J ) 7.5 and 7.3 Hz, 1H), 7.27 (dd, J ) 7.7 and 1.0 Hz,
1H), 7.32 (ddd, J ) 8.5, 7.2, and 1.4 Hz, 1H), 7.41 (br s, 1H), 7.61 (d,
J ) 7.7 Hz, 1H), 7.77 (br s, 1H), 8.00 (br s, 1H); HRMS calcd C23H24-
BrN2O4 (M+) 457.0889, found 457.0886. Anal. Calcd for C23H24-
BrNO4: C, 60.27; H, 5.28; N, 3.06. Found: C, 60.46; H, 5.39; N, 3.02.
1
a mixture of 26a and 26b. 26a, H NMR (CDCl3): δ 1.46 (s, 9H),
tert-Butyl 2-(2-Bromophenyl)-3-oxo-2-{3-[(trimethylsilyl)oxy]but-
3-enyl}indoline-1-carboxylate (24). A solution of dry diisopropylamine
(536 mg, 5.03 mmol) in dry THF (50 mL) was cooled to -78 °C, and
a solution of butyllithium in hexane (1.6 M, 3.06 mL, 4.9 mol) was
added. After being stirred for 10 min at -78 °C under N2, a solution
of 22 (1.87 g, 4.08 mmol) in THF (40 mL) was added to the resulting
lithium diisopropylamide/THF solution. After the complete consumption
of starting material, which was confirmed by thin-layer chromatography
(2:1 hexane/EtOAc), a solution of chlorotrimethylsilane in THF (1.0
M, 4.49 mL, 4.49 mmol) was added in the reaction mixture. After the
formation of 24 was confirmed by thin-layer chromatography (2:1
hexane/EtOAc), the reaction mixture was poured into 20% aqueous
NH4Cl solution (200 mL), and the resulting mixture was extracted with
EtOAc (4 × 80 mL). The combined extracts were washed with brine
(30 mL), dried over Na2SO4, and concentrated. The crude was purified
by chromatography (SiO2, 10:1 hexane/EtOAc) to afford 24 (1.69 g,
78%). IR: 3072, 3061, 2973, 2964, 2932, 1761, 1711, 1633, 1606,
1467, 1392, 1366, 1363, 1251, 1163, 1159, 1090, 1060, 1052, 1033,
2.01 (ddd, J ) 13.1, 13.1, and 6.2 Hz, 1H), 2.62 (ddd, J ) 13.1, 13.1,
and 6.2 Hz, 1H), 2.89 (dd, J ) 18.5 and 6.2 Hz, 1H), 3.81 (dd, J )
18.5 and 4.5 Hz, 1H), 6.49 (s, 1H), 7.06-7.12 (2H), 7.29-7.34 (2H),
7.51-7.55 (2H), 7.82-7.86 (2H); HRMS calcd C23H24BrN2O3 (MH+)
455.0970, found 455.0974. Anal. Calcd for C23H23Br N2O3: C, 60.67;
1
H, 5.09; N, 6.15. Found: C, 60.63; H, 5.46; N, 5.78. 26b, H NMR
(CDCl3) partial data, δ 7.02 (s, 1H); HRMS calcd C23H24BrN2O3 (MH+)
455.0970, found 455.0978. Anal. Calcd for C23H23BrN2O3: C, 60.67;
H, 5.09; N, 6.15. Found: C, 60.63; H, 5.51; N, 5.75.
Preparation of 26 in Pyridine. Hydroxylamine hydrochloride (116
mg, 1.67 mmol) was added to a solution of 25 (487 mg, 1.11 mmol)
in pyridine (5 mL), and the resulting mixture was stirred at room
temperature for 3.5 h. The reaction mixture was partitioned between
EtOAc (50 mL) and H2O (50 mL), and the layers were separated. The
aqueous layer was extracted with EtOAc (50 mL), and the combined
organic layers were dried over MgSO4, filtered, and concentrated. The
crude product was a 55:45 mixture of 26a and 26b and was clean when
analyzed by NMR. It was used without purification.
1
928, 868, 846, 744 cm-1. H NMR (C6D6): 0.12 (s, 9H, SiMe3), 1.15
(s, 9H), 2.09 (ddd, J ) 13.5, 12.8, and 4.7 Hz, 1H), 2.19 (ddd, J )
13.5, 12.8, and 4.7 Hz, 1H), 2.94 (ddd, J ) 13.1, 12.8, and 4.7 Hz,
1H), 3.07 (m, 1H), 3.97 (d, J ) 1.0 Hz, 1H), 4.07 (d, J ) 1.0 Hz, 1H),
6.59 (ddd, J ) 7.6, 7.5, and 1.5 Hz, 1H), 6.68 (dd, J ) 7.7 and 7.6 Hz,
1H), 6.87 (dd, J ) 7.6 and 7.3 Hz, 1H), 7.19-7.23 (2H), 7.58 (d, J )
7.1 Hz, 1H), 7.72 (d, J ) 7.7 Hz, 1H), 8.71 (br s, 1H); ESI-MS m/z
530 (MH+); HRMS calcd for C23H24BrNO4Si (M - SiMe3 + H+)
457.0889, found 457.0886.
tert-Butyl 5a-(2-Bromophenyl)-2-oxo-3,4,5,5a-tetrahydroazepino-
[4,5-b]indole-6(2H)-carboxylate (28). To a solution of 26 (101 mg,
0.221 mmol) in anhydrous pyridine was added tosyl chloride (62.4 mg,
0.327 mmol). The reaction mixture was stirred at room temperature
for 17 h, and then it was partitioned between EtOAc (25 mL) and
saturated aqueous NaHCO3 (25 mL). The layers were separated, and
the organic layer was washed with H2O (25 mL), dried over MgSO4,
filtered, and concentrated to yield 27 [olefinic proton signals for 27a,
1
1H NMR (CDCl3) δ 6.41 (s, 1H), and 27b, H NMR (CDCl3) δ 6.86
Preparation of 23 from 24. To a solution of 24 (1.60 g, 3 mmol)
in a mixed solvent of 4:1 methylene chloride/methanol (50 mL) was
added 230-400 mesh ASTM silica gel (10 g). The mixture was
evaporated under reduced pressure and kept at room temperature for
16 h. Chromatography of the mixture (SiO2, 7:3 hexane/EtOAc as
mobile phase) afforded 23 (344 mg, 25%).
(s, 1H)]. Crude 27 (111 mg) was heated in EtOH (5 mL) for 3 h. The
reaction mixture was concentrated, and the residue was chromato-
graphed (SiO2, 4:1 hexane/EtOAc followed by 1:1 hexane/EtOAc
followed by 1:2 hexane/EtOAc) to yield 28 (18.6 mg) in 19% yield.
IR: 3138, 3098, 3052, 2976, 2895, 2867, 1725, 1710, 1676, 1646, 1615,
1604, 1475, 1390, 1378, 1374, 1297, 1253, 1248, 1231, 1206, 1165,
757, 750 cm-1. 1H NMR (CDCl3): δ 1.16 (s, 9H), 2.57 (dd, J ) 13.1
and 7.9 Hz, 1H), 2.65 (dd, J ) 14.6 and 11.1 Hz, 1H), 2.90 (ddd, J )
13.1, 11.0, and 10.8 Hz, 1H), 3.89 (br s, 1H), 5.98 (s, 1H), 6.43 (d, J
) 2.9 Hz, 1H), 7.06 (dd, J ) 7.9 and 7.9 Hz, 1H), 7.15 (dd, J ) 8.3
and 8.3 Hz, 1H), 7.32 (dd, J ) 7.7 and 7.7 Hz, 1H), 7.36 (dd, J ) 7.8
and 7.8 Hz, 1H), 7.41 (d, J ) 7.7 Hz, 1H), 7.53 (d, J ) 7.7 Hz, 1H),
7.80 (d, J ) 8.1 Hz, 1H), 8.00 (br s, 1H); HRMS calcd C23H24BrN2O3
(MH+) 455.0971, found 455.0960. Anal. Calcd for C23H23BrN2O3: C,
60.67; H, 5.09; N, 6.15. Found: C, 60.26; H, 5.26; N, 5.78.
tert-Butyl 9a-(2-Bromophenyl)-3-oxo-1,2,3,9a-tetrahydro-9H-car-
bazole-9-carboxylate (25). A solution of 23 (630 mg, 1.37 mmol) in
dry pyridine (20 mL) was stirred at 0 °C, and methansulfonyl chloride
(785 mg, 6.85 mmol) was added. After being stirred at 0 °C for 30
min, the reaction mixture was allowed to warm and was stirred at room
temperature for 20 h. The reaction mixture was poured into NH4Cl
solution (200 mL), acidified with 2 N HCl solution to pH ) 2, and
extracted with EtOAc (4 × 60 mL). The combined extracts were washed
with saturated Na2CO3 solution (2 × 20 mL), dried over Na2SO4, and
concentrated. The crude product was purified by chromatography (SiO2,
3.4:1 hexane/EtOAc) to afford 25 (460 mg, 76%). IR: 3073, 3045,
3018, 2985-2928 (br), 2887, 2853, 1708, 1663, 1656, 1620, 1600,
1393, 1366, 1270, 1247, 1229, 1200, 1161, 1007, 928, 880, 763, 759
tert-Butyl 2-(2-Bromophenyl)-2-(2-hydroxyethyl)-3-oxoindoline-
1-carboxylate (29). Olefin 15 (2.66 g, 6.21 mmol) was dissolved in
ethanol (100 mL) and cooled to -78 °C under N2. O3, from an ozone
generator, was bubbled through the reaction mixture until a faint blue
color appeared in the reaction mixture. Complete consumption of
starting material was confirmed using thin-layer chromatography (4:1
hexane/EtOAc). After being bubbled with N2 for 15 min, the reaction
mixture was diluted with THF (50 mL), and NaBH4 (235 mg, 6.21
1
cm-1. UV λmax 255 (12 700), 299 (7620), 385 (6780) nm. H NMR
(CDCl3): δ 1.47 (s, 9H), 2.31 (m, 1H), 2.55-2.59 (2H), 3.90 (br d, J
) 13.7 Hz, 1H), 6.29 (s, 1H), 7.11-7.16 (2H), 7.35 (ddd, J ) 7.6,
7.1, and 1.5 Hz, 1H), 7.47 (ddd, J ) 7.8, 7.3, and 1.2 Hz, 1H), 7.55
(dd, J ) 7.9 and 1.5 Hz, 1H), 7.60 (d, J ) 7.7 Hz, 1H), 7.87-7.94
9
4248 J. AM. CHEM. SOC. VOL. 125, NO. 14, 2003

Synthesis of 8-Desbromohinckdentine A
A R T I C L E S
mmol) was added. The reaction mixture was warmed to room
temperature and stirred for 2 h. An additional portion of NaBH4 (235
mg, 6.21 mmol) was added to the reaction mixture, and it was stirred
for another 5 h. The reaction mixture was concentrated, diluted with
saturated NH4Cl solution (100 mL), and extracted with EtOAc (4 ×
50 mL). The combined extracts were washed with saturated Na2CO3
solution (2 × 10 mL), dried over Na2SO4, and concentrated. The crude
product was purified by chromatography (SiO2, 2:1 hexane/EtOAc) to
afford 29 (2.63 g, 98%). IR: 3429 (br), 2976, 2932, 2888, 1710, 1607,
1592, 1467, 1393, 1367, 1324, 1305, 1266, 1253, 1164, 1069, 1054,
3.9 Hz, 1H), 2.92 (ddd, J ) 11.8, 11.0, and 3.9 Hz, 1H), 7.25-7.30
(2H), 7.50 (ddd, J ) 7.8, 7.5, and 0.8 Hz, 1H), 7.57 (dd, J ) 7.9 and
1.3 Hz, 1H), 7.71-7.83 (3H), 8.29 (d, J ) 7.1 Hz, 1H); HRMS calcd
C21H24BrN2O3 (MH+) 431.0970, found 431.0970.
tert-Butyl 2-[2-(Acetylamino)ethyl]-2-(2-bromophenyl)-3-oxoin-
doline-1-carboxylate (33). A solution of 32 (1.70 g, 3.94 mmol) in
dry pyridine (50 mL) was stirred at 0 °C, and acetic anhydride (2.01 g,
19.70 mmol) was added. After being stirred at 0 °C for 30 min, the
reaction mixture was allowed to warm to room temperature and was
stirred for 20 h. The reaction mixture was poured into saturated NH4-
Cl solution (150 mL), acidified with 2 N HCl solution to pH ) 2, and
extracted with EtOAc (4 × 50 mL). The combined extracts were washed
with saturated Na2CO3 solution (2 × 10 mL), dried over Na2SO4, and
concentrated. The crude product was purified by chromatography (SiO2,
5:6 hexane/EtOAc) to afford 33 (1.83 g, 98%). IR: 3294, 3090, 2977,
2950, 1710, 1676, 1662, 1656, 1645, 1606, 1467, 1433, 1392, 1365,
1360, 1266, 1252, 1162, 768, 756 cm-1. 1H NMR (CDCl3): δ 1.25 (s,
9H), 1.88 (s, 3H), 2.69 (ddd, J ) 13.3, 6.6, and 6.6 Hz, 1H), 2.92
(ddd, J ) 13.3, 6.6 and 6.6 Hz, 1H), 3.12-3.27 (2H), 5.32 (br s, 1H,
NH), 7.17-7.24 (2H), 7.41 (ddd, J ) 7.7, 7.5, and 1.5 Hz, 1H), 7.53
(ddd, J ) 7.9 and 1.3 Hz, 1H), 7.70-7.75 (2H), 7.78 (ddd, J ) 7.7,
1.3, and 0.6 Hz, 1H), 8.35 (br s, 1H); HRMS calcd C23H26BrN2O4
(MH+) 473.1076, found 473.1084. Anal. Calcd for C23H25BrN2O4: C,
58.36; H, 5.32; N, 5.92; Found: C, 58.31; H, 5.38; N, 5.77.
1
1038, 1023, 773, 756, 747 cm-1. H NMR (CDCl3): δ 1.25 (s, 9H),
2.77 (ddd, J ) 13.3, 6.8 and 6.8 Hz, 1H), 2.95 (m, 1H), 3.55-3.67
(2H), 7.18-7.21 (2H), 7.42 (ddd, J ) 7.7, 7.5, and 1.3 Hz, 1H), 7.53
(dd, J ) 7.9 and 1.3 Hz, 1H), 7.68-7.73 (2H), 7.78 (dd, J ) 7.7 and
0.8 Hz, 1H), 8.32 (br s, 1H); HRMS calcd C21H23BrNO4 (MH+)
432.0811, found 432.0808. Anal. Calcd for C21H22BrNO4: C, 58.34;
H, 5.13; N, 3.24. Found: C, 58.51; H, 5.33; N, 3.37.
tert-Butyl 2-(2-Bromophenyl)-2-{2-[(methylsulfonyl)oxy]ethyl}-
3-oxoindoline-1-carboxylate (30). A solution of 29 (2.50 g, 5.78 mmol)
in dry pyridine (50 mL) was stirred at 0 °C, and methanesulfonyl
chloride (1.06 g, 9.25 mmol) was added. After being stirred at 0 °C
for 1 h, the reaction mixture was allowed to warm to room temperature
and was stirred for 2 h. The reaction mixture was poured into saturated
NH4Cl solution (150 mL), acidified with 2 N HCl solution to pH ) 2,
and extracted with EtOAc (4 × 50 mL). The combined extracts were
washed with saturated Na2CO3 solution (2 × 10 mL), dried over Na2-
SO4, and concentrated. The crude product was purified by chromatog-
raphy (SiO2, 8:3 hexane/EtOAc) to afford 30 (2.60 g, 88%). IR: 3075,
3023, 2977, 2934, 2906, 1711, 1605, 1467, 1393, 1366, 1361, 1267,
tert-Butyl 2-{2-[Acetyl(tert-butoxycarbonyl)amino]ethyl}-2-(2-
bromophenyl)-3-oxoindoline-1-carboxylate (34). To a magnetically
stirred solution of 33 (1.75 g, 3.70 mmol) and 4-(dimethylamino)-
pyridine (2.26 g, 18.50 mmol) in acetonitrile (100 mL) was added a
solution of di-tert-butyl dicarbonate (3.23 g, 14.80 mmol) in acetonitrile
(50 mL). After being stirred for 17 h under N2, the reaction mixture
was concentrated under reduced pressure, and the residue was
partitioned between EtOAc (100 mL) and saturated NH4Cl solution
(120 mL). The aqueous phase was extracted with EtOAc (3 × 40 mL).
The combined extracts were washed with saturated NaHCO3 solution,
dried over Na2SO4, and concentrated. The crude product was chro-
matographed (SiO2, 10:1 hexane:EtOAc) to afford 34 (2.04 g, 96%).
IR: 3008, 2977, 2933, 1734, 1714, 1694, 1607, 1467, 1449, 1392, 1308,
1265, 1221, 1198, 1167, 764, 748 cm-1. 1H NMR (CDCl3): δ 1.27 (s,
9H), 1.48 (s, 9H), 2.47 (s, 3H), 2.56 (ddd, J ) 12.3, 12.3, and 4.8 Hz,
1H), 2.82 (ddd, J ) 12.3, 12.3, and 4.8 Hz, 1H), 3.37 (ddd, J ) 12.9,
12.3, and 4.8 Hz, 1H), 3.82 (ddd, J ) 12.9, 12.3, and 4.8 Hz, 1H),
7.17-7.21 (2H), 7.42 (ddd, J ) 7.1, 7.6, and 1.5 Hz, 1H), 7.52 (dd, J
) 7.9 and 1.3 Hz, 1H), 7.70 (ddd, J ) 7.8, 7.3, and 1.3 Hz, 1H), 7.77
(d, J ) 7.5 Hz, 1H), 7.80 (d, J ) 8.1 Hz, 1H), 8.35 (br s, 1H); HRMS
calcd C28H34BrN2O6 (MH+) 573.1600, found 573.1609. Anal. Calcd
for C28H33BrN2O6: C, 58.64; H, 5.80; N, 4.88; Found: C, 58.33; H,
5.90; N, 4.79.
1
1252, 1199, 1177, 773, 757 cm-1. H NMR (CDCl3): δ 1.27 (s, 9H),
2.79 (s, 3H), 2.97 (ddd, J ) 13.9, 6.2, and 6.2 Hz, 1H), 3.15 (m, 1H),
4.08-4.23 (2H), 7.20-7.25 (2H), 7.43 (ddd, J ) 7.7, 7.7, and 1.5 Hz,
1H), 7.55 (dd, J ) 7.9 and 1.3 Hz, 1H), 7.63 (dd, J ) 8.0 and 1.0 Hz,
1H), 7.73 (ddd, J ) 7.9, 7.5, and 1.5 Hz, 1H), 8.05 (dd, J ) 7.7 and
0.6 Hz, 1H), 8.34 (br s, 1H); HRMS calcd C22H25BrNO6S (MH+)
510.0586, found 510.0605.
tert-Butyl 2-(2-Azidoethyl)-2-(2-bromophenyl)-3-oxoindoline-1-
carboxylate (31). To a solution of 30 (2.5 g, 4.9 mmol) in DMF (50
mL) was added sodium azide (2.55 g, 39.2 mmol), and the reaction
mixture was heated at 95 °C for 20 h. After being cooled to room
temperature, the reaction mixture was partitioned between water (200
mL) and EtOAc (200 mL), and the aqueous layer was extracted with
EtOAc (3 × 40 mL). The combined extracts were washed with brine,
dried over Na2SO4, and concentrated. The crude product was purified
by chromatography (SiO2, 10:31 hexane/EtOAc) to afford 31 (2.17 g,
97%). IR: 3082, 3061, 3005, 2995, 2980, 2959, 2930, 2145, 2094,
2091, 1711, 1603, 1468, 1391, 1364, 1361, 1265, 1250, 1164, 1155,
772, 761, 755, 745 cm-1. 1H NMR (CDCl3): δ 1.26 (s, 9H), 2.75 (ddd,
J ) 13.1, 7.5 and 7.5 Hz, 1H), 2.95 (m, 1H), 3.18 (t, J ) 7.3 Hz, 1H),
7.19-7.25 (2H), 7.43 (ddd, J ) 7.7, 7.5, and 1.5 Hz, 1H), 7.54 (dd, J
) 7.9 and 1.3 Hz, 1H), 7.65 (dd, J ) 8.1 and 1.3 Hz, 1H), 7.73 (ddd,
J ) 7.9, 7.3, and 1.5 Hz, 1H), 7.79 (ddd, J ) 7.7, 1.5, and 0.8 Hz,
1H), 8.33 (br s, 1H); HRMS calcd C21H22BrN4O3 (MH+) 457.0876,
found 457.0890.
tert-Butyl 2-(2-Bromophenyl)-2-{2-[(2,5-dimethoxybenzyl)amino]-
ethyl}-3-oxo-2,3-dihydro-1H-indole-1-carboxylate (36). Olefin 15
(11.3 g, 26.38 mmol) was dissolved in methanol (280 mL) and cooled
to -78 °C under N2. O3, from an ozone generator, was bubbled through
the reaction mixture until a faint blue color appeared in the reaction
mixture. Complete consumption of starting material was confirmed
using thin-layer chromatography (4:1 hexane/EtOAc). After the mixture
was bubbled with N2 for 15 min, methyl sulfide (19.4 mL, 263.8 mmol)
was added, and the reaction mixture was allowed to warm to room
temperature during 1.5 h. This solution was concentrated and diluted
with methanol/THF (1:1, 400 mL), and the resulting solution was cooled
to 0 °C. 2,4-Dimethoxybenzylamine (22.0 g, 131.9 mmol) followed
by acetic acid (17.4 g, 290 mmol) was added to the reaction mixture,
which was stirred at 0 °C for 30 min. NaCNBH3 (3.29 g, 52.36 mmol)
was added to the reaction mixture. The reaction mixture was warmed
to room temperature and stirred for 6 h. An additional portion of
NaCNBH3 (1.68 g, 26.7 mmol) was added to the reaction mixture that
was stirred for another 10 h. The reaction mixture was concentrated,
diluted with water (300 mL), and extracted with EtOAc (4 × 100 mL).
tert-Butyl 2-(2-Aminoethyl)-2-(2-bromophenyl)-3-oxoindoline-1-
carboxylate (32). A solution of 31 (2 g, 4.37 mmol) in EtOAc (100
mL) was stirred at room temperature under H2 (atmospheric pressure)
for 18 h. The reaction mixture was filtered through Celite, and the
filtrate was evaporated. The residue was diluted with a mixture of
methylene chloride (100 mL) and a saturated solution of NH3 in MeOH
(40 mL) and evaporated again. The crude product was purified by
chromatography (SiO2, 10:1 CH2Cl2/MeOH) to afford 32 (1.87 g, 99%).
IR: 3381, 3312, 3188, 3062, 2976, 2932, 2910, 2971, 1710, 1604, 1467,
1
1392, 1366, 1361, 1265, 1251, 1161, 770, 756 cm-1. H NMR (CD3-
OD): δ 1.25 (s, 9H), 2.41 (ddd, J ) 11.8, 11.0, and 3.9 Hz, 1H), 2.52
(ddd, J ) 11.8, 11.0, and 3.9 Hz, 1H), 2.61 (ddd, J ) 11.8, 11.0, and
9
J. AM. CHEM. SOC. VOL. 125, NO. 14, 2003 4249

A R T I C L E S
Liu and McWhorter
The combined extracts were washed with saturated Na2CO3 solution
(2 × 50 mL), dried over Na2SO4, and concentrated. The crude product
was purified by chromatography (SiO2, 6:5 hexane/EtOAc) to afford
36 (9.14 g, 60%). IR: 3073, 2974, 2934, 2834, 1710, 1608, 1589, 1506,
1467, 1392, 1365, 1362, 1288, 1252, 1207, 1157, 1098, 1069, 1036,
835, 770, 756 cm-1. 1H NMR (CDCl3): δ 1.22 (s, 9H), 2.39 (ddd, J )
11.1, 10.6, and 5.5 Hz, 1H), 2.50 (ddd, J ) 11.1, 10.6, and 4.8 Hz,
1H), 2.65 (ddd, J ) 12.9, 10.6, and 5.5 Hz, 1H), 2.93 (ddd, J ) 11.1,
10.6, and 4.8 Hz, 1H), 3.53 (d, J ) 13.0 Hz, 1H), 3.57 (d, J ) 13.0
Hz, 1H), 3.75 (s, 3H), 3.80 (s, 3H), 6.37-6.41 (2H), 6.99 (d, J ) 8.1
Hz, 1H), 7.16-7.19 (2H), 7.39 (ddd, J ) 7.9, 7.3, and 1.3 Hz, 1H),
7.52 (dd, J ) 7.9 and 1.3 Hz, 1H), 7.68 (ddd, J ) 7.9, 7.3, and 1.3 Hz,
1H), 7.71-7.73 (2H), 8.31 (br s, 1H); HRMS calcd C30H34BrN2O5
(MH+) 581.1652, found 581.1660. C30H33BrN2O5: C, 61.97; H, 5.72;
N, 4.82. Found: C, 61.92; H, 5.83; N, 4.83.
and 7.3 Hz, 1H), 7.19 (dd, J ) 7.3 and 7.3 Hz, 1H), 7.40-7.45 (2H),
7.50 (d, J ) 6.8 Hz, 1H), 7.56 (d, J ) 6.8 Hz, 1H), 7.64 (d, J ) 7.3
Hz, 1H), 8.13 (d, J ) 6.8 Hz, 1H); HRMS calcd C32H36BrN2O6 (MH+)
623.1757, found 623.1771. Anal. Calcd for C32H35BrN2O6: C, 61.64;
H, 5.66; N, 4.49. Found: C, 61.49; H, 5.80; N, 4.54.
tert-Butyl 5a-(2-Bromophenyl)-3-(2,4-dimethoxybenzyl)-2-oxo-
3,4,5,5a-tetrahydroazepino[4,5-b]indole-6(2H)-carboxylate (39). A
solution of 38 (7.89 g, 12.65 mmol) in dry pyridine (150 mL) was
stirred at 0 °C, and methansulfonyl chloride (7.25 g, 63.25 mmol) was
added. After being stirred at 0 °C for 30 min, the reaction mixture was
allowed to warm to room temperature and was stirred for 20 h. The
reaction mixture was poured into saturated NH4Cl solution (400 mL),
acidified with 6 N HCl solution to pH ) 2, and extracted with EtOAc
(4 × 150 mL). The combined extracts were washed with saturated
NaHCO3 solution (2 × 60 mL), dried over Na2SO4, and concentrated.
The crude product was purified by chromatography (SiO2, 6:5 hexane/
EtOAc) to afford 39 (7.36 g, 96%). IR: 2976, 2933, 2835, 1706, 1653,
1618, 1588, 1506, 1475, 1379, 1367, 1291, 1262, 1250, 1208, 1160,
1093, 1068, 1033, 1020, 844, 754 cm-1. 1H NMR (CDCl3): δ 1.24 (br
s, 9H), 2.15 (dd, J ) 14.9 and 6.7 Hz, 1H), 3.49 (dd, J ) 14.9 and 6.8
Hz, 1H), 3.66 (m, 1H), 3.82 (s, 3H), 3.91 (s, 3H), 4.09 (m, 1H), 4.15
(d, J ) 14.7 Hz, 1H), 4.71 (d, J ) 14.7 Hz, 1H), 6.35 (s, 1H), 6.46
(dd, J ) 8.4 and 2.5 Hz, 1H), 6.50 (d, J ) 2.1 Hz, 1H), 7.10-7.14
(2H), 7.19 (d, J ) 8.4 Hz, 1H), 7.32 (dd, J ) 7.6 and 7.6 Hz, 1H),
7.42 (dd, J ) 7.6 and 7.6 Hz, 1H), 7.51 (d, J ) 7.6 Hz, 1H), 7.56 (d,
J ) 7.6 Hz, 1H), 7.71 (d, J ) 7.6 Hz, 1H), 8.13 (br, 1H); HRMS calcd
C32H34BrN2O5 (MH+) 605.1652, found 605.1636. Anal. Calcd for
C32H33BrN2O5: C, 63.47; H, 5.49; N, 4.63; Found: C, 63.06; H, 5.61;
N, 4.48.
tert-Butyl 2-{2-[Acetyl(2,4-dimethoxybenzyl)amino]ethyl}-2-(2-
bromophenyl)-3-oxoindoline-1-carboxylate (37). A solution of 36 (9.0
g, 15.5 mmol) in dry pyridine (100 mL) was stirred at 0 °C, and acetic
anhydride (7.92 g, 77.5 mmol) was added. After being stirred at 0 °C
for 30 min, the reaction mixture was allowed to warm to room
temperature and was stirred for 20 h. The reaction mixture was poured
into saturated NH4Cl solution (400 mL), acidified with 2 N HCl solution
to pH ) 2, and extracted with EtOAc (4 × 150 mL). The combined
extracts were washed with saturated Na2CO3 solution (2 × 50 mL),
dried over Na2SO4, and concentrated. The crude product was purified
by chromatography (SiO2, 3:2 hexane/EtOAc) to afford 37 (8.79 g,
91%). IR: 3073, 3000, 2974, 2933, 2836, 1711, 1645, 1609, 1589,
1507, 1467, 1392, 1360, 1291, 1265, 1250, 1209, 1158, 1121, 1072,
1
1033, 838, 757 cm-1. H NMR (CDCl3) δ 1.23 (br s, 9H), 2.04 (s,
1.2H), 2.15 (s, 1.8H), 2.54 (ddd, J ) 11.8, 11.4, and 3.7 Hz, 0.6H),
2.73 (ddd, J ) 12.2, 12.2, and 4.6 Hz, 0.6H), 2.77 (ddd, J ) 12.0,
12.0, and 4.6 Hz, 0.4H), 2.88-3.03 (1.4H), 3.17 (m, 0.4H), 3.53 (ddd,
J ) 13.1, 11.4, and 4.6 Hz, 0.6H), 3.76 (s, 1.8H), 3.78 (s, 1.8H), 3.78
(s, 1.2H), 3.79 (s, 1.2H), 4.25 (d, J ) 16.2 Hz, 0.6H), 4.36 (d, J )
16.4 Hz, 0.6H), 4.45 (d, J ) 14.1 Hz, 0.4H), 4.53 (d, J ) 14.7 Hz,
0.4H), 6.35 (dd, J ) 8.3 and 2.3 Hz, 0.6H), 6.39-6.42 (1.4H), 6.84
(d, J ) 8.3 Hz, 0.6H), 7.14-7.28 (2.4H), 7.40-7.45 (1H), 7.50 (dd, J
) 7.9 and 1.3 Hz, 0.6H), 7.54 (dd, J ) 7.9 and 1.2 Hz, 0.4H), 7.62-
7.75 (2.4H), 7.91 (d, J ) 7.9 Hz, 0.6H), 8.30 (br s, 1H); HRMS calcd
C32H36BrN2O6 (MH+) 623.1757, found 623.1772. Anal. Calcd for
C32H35BrN2O6: C, 61.64; H, 5.66; N, 4.49; Found: C, 61.64; H, 5.84;
N, 4.51.
tert-Butyl 5a-(2-Bromophenyl)-3-(2,4-dimethoxybenzyl)-2-oxo-
2,3,4,5,5a,10b-hexahydroazepino[4,5-b]indole-6(1H)-carboxylate (40).
To a solution of 39 (6.28 g, 10.37 mmol) in MeOH (180 mL) were
added magnesium turnings (2.48 g, 103.7 mmol), and the reaction
mixture was stirred at room temperature under N2. After an induction
period, a very vigorous exothermic reaction ensued, which was
controlled using an ice-water bath. After being stirred for 24 h, the
reaction mixture was concentrated under reduced pressure, diluted with
EtOAc (200 mL), and washed with 20% NH4Cl solution (200 mL).
The aqueous wash was extracted with EtOAc (3 × 40 mL), and the
combined EtOAc layers were washed with saturated NaHCO3 solution
(2 × 20 mL) and brine (20 mL). After being dried over Na2SO4, the
EtOAc solution of the crude product was filtered and concentrated.
The crude product was purified by chromatography (SiO2, 7:4 hexane/
EtOAc) to furnish 40 (4.98 g, 79%). IR: 3095-3018, 2998-2903,
2880, 2833, 1701, 1626, 1586, 1498, 1490, 1467, 1440, 1386, 1359,
1285, 1268, 1258, 1239, 1207, 1179, 1168, 1158, 1081, 1043, 1030,
tert-Butyl 5a-(2-Bromophenyl)-3-(2,4-dimethoxybenzyl)-10b-hy-
droxy-2-oxo-2,3,4,5,5a,10b-hexahydroazepino[4,5-b]indole-6(1H)-
carboxylate (38). A solution of dry diisopropylamine (1.83 g, 18.1
mmol) in dry THF (200 mL) was cooled to -78 °C, and a solution of
butyllithium in hexane (1.6 M, 10.43 mL, 16.68 mmol) was added.
After being stirred for 10 min at -78 °C under N2, a solution of 37
(8.68 g, 13.90 mmol) in THF that had been cooled to -78 °C was
added to the lithium diisopropylamide/THF solution. After the complete
consumption of starting material, which was confirmed by thin-layer
chromatography (1:2 hexane/EtOAc), the reaction mixture was poured
into a solution of acetic acid (4.2 g, 69.5 mmol) in THF (200 mL) at
-78 °C. The resulting mixture was concentrated under reduced pressure,
and the residue was partitioned between water (200 mL) and EtOAc
(200 mL). The aqueous layer was neutralized with saturated Na2CO3
solution and extracted with EtOAc (4 × 40 mL). The combined extracts
were washed with brine (40 mL), dried over Na2SO4, and concentrated.
The crude product was purified by chromatography (SiO2, 3:8 hexane/
EtOAc) to afford 38 (7.99 g, 92%). IR: 3562, 3550, 3543, 3373, 3066,
3056, 2998, 2971, 2933, 2835, 1732, 1727, 1701, 1627, 1615, 1590,
1
836, 765, 754 cm-1. H NMR (CDCl3): δ 1.09 (br s, 9H), 1.43 (br,
1H), 2.62 (br, 1H), 3.00-3.37 (4H), 3.72 (s, 3H), 3.79 (s, 3H), 4.19
(m, 1H), 4.24 (d, J ) 15.1 Hz, 1H), 4.60 (d, J ) 15.1 Hz, 1H), 6.24
(d, J ) 7.5 Hz, 1H), 6.37 (d, J ) 2.3 Hz, 1H), 6.43 (m, 1H), 7.08 (dd,
J ) 7.4 and 7.4 Hz, 1H), 7.18 (dd, J ) 7.4 and 7.4 Hz, 1H), 7.29-
7.42 (3H), 7.50 (d, J ) 6.6 Hz, 1H), 7.68 (d, J ) 7.7 Hz, 1H), 7.97
(br, 1H); HRMS calcd C32H36BrN2O5 (MH+) 607.1808, found 607.1813.
Anal. Calcd for C32H35BrN2O5: C, 63.26; H, 5.81; N, 4.61; Found: C,
63.66; H, 5.95; N, 4.62.
tert-Butyl 3-(2,4-Dimethoxybenzyl)-5a-{2-[(diphenylmethylene)-
amino]phenyl}-2-oxo-2,3,4,5,5a,10b-hexahydroazepino[4,5-b]indole-
6(1H)-carboxylate (41). A pressure tube was charged with 40 (3.76
g, 6.19 mmol), benzophenone imine (1.46 g, 8.05 mmol), Pd(DPPF)2Cl2
(22.7 mg, 0.031 mmol), DPPF (25.5 mg, 0.046 mmol), sodium tert-
butoxide (833 mg, 8.67 mmol), and dry toluene (20 mL) and purged
with argon gas. The pressure tube was sealed and heated in a 140 °C
bath for 24 h. After being cooled to room temperature, the reaction
mixture was chromatographed (SiO2, 8:3 hexane/EtOAc) to afford 41
(2.72 g, 62%). IR: 3060, 2995, 2972, 2932, 1694, 1630, 1615, 1590,
1570, 1504, 1482, 1459, 1366, 1317, 1289, 1256, 1207, 1157, 1132,
1504, 1466, 1461, 1372, 1369, 1289, 1252, 1207, 1164, 1159, 756 cm-1
.
1H NMR (CDCl3): δ 1.12 (s, 9H), 1.53 (br s, 1H), 2.82 (br m, 1H),
3.20 (br s, 1H), 3.25 (br s, 1H), 3.38 (d, J ) 17.6 Hz, 1H), 3.53 (d, J
) 17.6 Hz, 1H), 3.73 (s, 3H), 3.80 (s, 3H), 4.13 (d, J ) 15.3 Hz, 1H),
4.54 (d, J ) 15.3 Hz, 1H), 6.22 (s, 2H), 6.35 (s, 1H), 7.14 (dd, J ) 7.3
9
4250 J. AM. CHEM. SOC. VOL. 125, NO. 14, 2003

Synthesis of 8-Desbromohinckdentine A
A R T I C L E S
1
749, 696 cm-1. H NMR (CDCl3): δ 1.35 (s, 9H), 2.90-3.35 (6H),
3H), 3.62 (d, J ) 12.7 and 3.1 Hz, 1H), 3.77 (s, 3H), 4.12 (br, 1H),
4.27 (d, J ) 14.5 Hz, 1H), 4.57 (d, J ) 14.5 Hz, 1H), 6.25 (dd, J )
8.3 and 2.3 Hz, 1H), 6.33 (d, J ) 2.3 Hz, 1H), 6.80 (d, J ) 8.3 Hz,
1H), 7.12-7.21 (2H), 7.24 (dd, J ) 7.3 and 7.1 Hz, 1H), 7.30-7.41
(4H), 7.57 (d, J ) 7.5 Hz, 1H), 8.08 (s, 1H); HRMS calcd C28H28N3O3
(MH+) 454.2131, found 454.2114. Anal. Calcd for C28H27N3O3: C,
74.15; H, 6.00; N, 9.26; Found: C, 73.56; H, 6.17; N, 9.02.
3.70 (s, 3H), 3.77 (s, 3H), 4.10 (d, J ) 15.4 Hz, 1H), 4.46 (br s, 1H),
4.59 (d, J ) 15.4 Hz, 1H), 6.18 (dd, J ) 8.5 and 2.4 Hz, 1H), 6.26 (d,
J ) 8.5 Hz, 1H), 6.27 (br s, 1H), 6.34 (d, J ) 2.4 Hz, 1H), 6.82-6.98
(4H), 7.06-7.47 (13H); HRMS calcd C45H46N3O5 (MH+) 708.3437,
found 708.3433.
tert-Butyl 5a-(2-Aminophenyl)-3-(2,4-dimethoxybenzyl)-2-oxo-
2,3,4,5,5a,10b-hexahydroazepino[4,5-b]indole-6(1H)-carboxylate
(42). To a solution of 41 (1.19 g, 1.68 mmol) in THF (60 mL) was
added 2 N aqueous HCl solution (3 mL). After being stirred at room
temperature for 2 h, the reaction mixture was concentrated under
reduced pressure, then diluted with EtOAc (100 mL) and washed with
saturated Na2CO3 (50 mL) solution. The aqueous wash was extracted
with EtOAc (3 × 20 mL), and the combined EtOAc layers were dried
over Na2SO4 and concentrated. The crude product was chromatographed
(SiO2, 7:4 hexane/EtOAc as mobile phase) to furnished 42 (1.47 g,
97%). IR: 3477, 3359, 3218, 3069, 3036, 3000, 2971, 2932, 2835,
1695, 1627, 1615, 1591, 1502, 1480, 1456, 1378, 1366, 1318, 1313,
11b,12,15,16-Tetrahydroazepino[4′,5′:2,3]indolo[1,2-c]quinazolin-
13(14H)-one (6). A solution of 44 (670 mg, 1.48 mmol) in formic
acid (10 mL) was heated in a 100 °C bath for 2 h. After being cooled
to room temperature, the reaction mixture was poured into saturated
Na2CO3 solution (150 mL) and extracted with EtOAc (4 × 60 mL).
The combined EtOAc solutions were washed with brine (20 mL), dried
over Na2SO4, and concentrated. The crude product was chromato-
graphed (SiO2, 10:1 EtOAc/MeOH) to afford 6 (417 mg, 93%). IR:
3200, 3085, 3065, 2945, 2881, 1663, 1273, 1233, 767, 748 cm-1. UV
λ
max 237 (12 400), 339 (14 500), 352 (9030) nm. 1H NMR (CDCl3): δ
1.90 (ddd, J ) 14.9, 8.7, and 1.6 Hz, 1H), 2.15 (ddd, J ) 14.9, 8.7,
and 1.6 Hz, 1H), 2.98 (dddd, J ) 14.9, 8.7, 3.9, and 1.6 Hz, 1H), 3.11
(dddd, J ) 14.9, 8.7, 5.4, and 1.6 Hz, 1H), 3.40 (ddd, J ) 16.0, 6.3,
and 1.5 Hz, 1H), 3.53 (dd, J ) 16.0 and 3.1 Hz, 1H), 4.14 (br dd, J )
6.3 and 3.1 Hz, 1H), 5.71 (br s, 1H), 7.07-7.14 (2H), 7.22-7.30 (2H),
7.35-7.39 (3H), 7.42 (d, J ) 7.5 Hz, 1H), 7.99 (s, 1H). 13C NMR
(CDCl3): δ 35.6, 36.9, 37.0, 46.3, 66.2, 108.8, 122.9, 124.4, 125.6,
126.0, 126.4, 129.2, 129.2, 129.8, 130.3, 140.4, 140.8, 142.1, 173.3;
HRMS calcd C19H18N3O (MH+) 304.1450, found 304.1449. Anal. Calcd
for C19H17N3O: C, 75.23; H, 5.65; N, 13.85. Found: C, 75.12; H, 5.65;
N, 13.79.
1289, 1258, 1207, 1158, 1091, 1079, 1036, 837, 751 cm-1. H NMR
1
(CDCl3): δ 1.15 (s, 9H), 2.43 (br s, 1H), 2.94-3.07 (2H), 3.17 (dd, J
) 15.6 and 6.6 Hz, 1H), 3.29 (dd, J ) 15.6 and 10.0 Hz, 1H), 3.41
(br s, 1H), 3.71 (s, 3H), 3.79 (s, 3H), 4.26 (d, J ) 15.1 Hz, 1H), 4.30
(d, J ) 5.2 Hz, 1H), 4.58 (d, J ) 15.1 Hz, 1H), 6.23 (dd, J ) 8.3 and
2.4 Hz, 1H), 6.37 (d, J ) 2.4 Hz, 1H), 6.44 (br s, 1H), 6.76 (d, J ) 7.5
Hz, 1H), 6.83 (dd,
J ) 7.7 and 7.5 Hz, 1H), 7.09-
7.17 (2H), 7.24 (d, J ) 7.7 Hz, 1H), 7.32 (dd, J ) 7.7 and 7.7 Hz,
1H), 7.40 (d, J ) 6.8 Hz, 1H), 7.92 (d, J ) 8.1 Hz, 1H); HRMS calcd
C32H38N3O5 (MH+) 544.2811, found 544.2828. Anal. Calcd for
C32H37N3O5: C, 70.70; H, 6.86; N, 7.73; Found: C, 70.40; H, 7.01;
N, 7.26.
2,10-Dibromo-11b,12,15,16-tetrahydroazepino[4′,5′:2,3]indolo-
[1,2-c]quinazolin-13(14H)-one (45). To a solution of 6 (50 mg, 0.165
mmol) in formic acid (4 mL) was added bromine (1055 mg, 6.6 mmol),
and the reaction mixture was stirred at room temperature for 48 h
(caution: pressure may develop). The reaction mixture was evaporated
under reduced pressure, and the residue was partitioned between 2 N
NaOH solution (50 mL) and EtOAc (40 mL). The aqueous layer was
extracted with EtOAc (3 × 20 mL), and the combined extracts were
washed with brine, dried over Na2SO4, and concentrated. The crude
product was chromatographed (SiO2, 10:1 EtOAc/MeOH) to afford 45
(70 mg, 92%). IR: 3340, 3066, 3020, 2978, 2946, 2926, 2847, 1680,
1662, 1638, 1601, 1574, 1543, 1481, 1464, 1315, 1265, 1235, 1205,
1068, 1063, 834, 811 cm-1. UV λmax 245 (11 200), 347 (18 500), 360
5a-(2-Aminophenyl)-3-(2,4-dimethoxybenzyl)-3,4,5,5a,6,10b-hexahy-
droazepino[4,5-b]indol-2(1H)-one (43). To a magnetically stirred
solution of 42 (1.32 g, 2.4 mmol) in methylene chloride (40 mL) was
added trifluoroacetic acid (10 mL) at 0 °C. The reaction mixture was
stirred at 0 °C for 30 min and at room temperature for 14 h. The reaction
mixture was partitioned between ice-cold 2 N NaOH (200 mL) and
EtOAc (200 mL). The aqueous layer was extracted with EtOAc (3 ×
50 mL), and the combined EtOAc extracts were washed with brine,
dried over Na2SO4, and concentrated. The crude product was chro-
matographed (SiO2, 6:5 hexane/EtOAc) to afford 43 (1.02 g, 95%).
IR: 3322, 3046, 3000, 2955, 2934, 2835, 1644, 1638, 1611, 1589, 1505,
1484, 1456, 1324, 1289, 1257, 1208, 1035, 834, 827, 751 cm-1. H
1
1
(12 500) nm. H NMR (CDCl3): δ 1.89 (dd, J ) 15.1 and 8.4, 1H),
NMR (CDCl3): δ 1.72 (dd, J ) 15.0 and 8.5 Hz, 1H), 2.43 (dd, J )
15.0 and 8.1 Hz, 1H), 2.86 (dd, J ) 15.2 and 2.1 Hz, 1H), 3.08 (dd, J
) 15.2 and 8.1 Hz, 1H), 3.51 (dd, J ) 14.9 and 7.7 Hz, 1H), 3.69 (m,
1H), 3.71 (s, 3H), 3.78 (s, 3H), 4.28 (br d, J ) 7.3 Hz, 1H), 4.34 (d,
J ) 14.6 Hz, 1H), 4.68 (d, J ) 14.6 Hz, 1H), 6.24 (dd, J ) 8.3 and 2.3
Hz, 1H), 6.38 (d, J ) 2.3 Hz, 1H), 6.71 (d, J ) 7.7 Hz, 1H), 6.76-
6.81 (3H), 6.90 (dd, J ) 7.4 and 7.3 Hz, 1H), 7.10-7.16 (3H), 7.37
(d, J ) 7.5 Hz, 1H); HRMS calcd C27H30N3O3 (MH+) 444.2287, found
444.2292. Anal. Calcd for C27H29N3O3: C, 73.11; H, 6.59; N, 9.47;
Found: C, 73.15; H, 6.72; N, 9.04.
2.16 (dd, J ) 14.6 and 8.4 Hz, 1H), 3.02 (ddd, J ) 14.9, 8.4, and 4.0
Hz, 1H), 3.15 (ddd, J ) 14.9, 8.4, and 5.6 Hz, 1H), 3.38 (dd, J ) 16.0
and 6.2 Hz, 1H), 3.49 (dd, J ) 16.0 and 2.9 Hz, 1H), 4.11 (br dd, J )
6.2 and 2.9 Hz, 1H), 6.06 (br s, 1H), 7.05 (d, J ) 6.0 Hz, 1H), 7.26 (d,
J ) 8.4 Hz, 1H), 7.42 (d, J ) 6.0 Hz, 1H), 7.44 (s, 1H), 7.49 (dd, J )
8.4 and 1.9 Hz, 1H), 7.56 (s, 1H), 8.01 (br s, 1H). 13C NMR (CDCl3):
δ 34.9, 36.3, 36.7, 45.6, 66.0, 110.0, 116.7, 118.9, 125.5, 127.2, 128.4,
131.4, 132.0, 132.1, 139.2, 140.0, 172.1 (two aromatic C’s are missing);
HRMS calcd C19H16Br2N3O (MH+) 459.9661, found 459.9657. Anal.
Calcd for C19H15Br2N3O: C, 49.49; H, 3.28; N, 9.11. Found: C, 49.40;
H, 3.40; N, 8.74.
14-(2,4-Dimethoxybenzyl)-11b,12,15,16-tetrahydroazepino[4′,5′:
2,3]indolo[1,2-c]quinazolin-13(14H)-one (44). To a solution of 43 (992
mg, 2.24 mmol) in 2-propanol (20 mL) was added formic acid (20
mL). The reaction mixture was stirred at 75 °C for 4 h. After being
cooled to room temperature, the reaction mixture was poured into
saturated Na2CO3 solution (300 mL) and extracted with EtOAc (4 ×
100 mL). The combined EtOAc solutions were washed with brine (30
mL), dried over Na2SO4, and concentrated. The crude product was
chromatographed (SiO2, EtOAc) to afford 44 (730 mg, 72%). IR: 3053,
3036, 2996, 2939, 2835, 1611, 1581, 1554, 1506, 1489, 1468, 1456,
Bromination of 2,10-Dibromo-11b,12,15,16-tetrahydroazepino-
[4′,5′:2,3]indolo[1,2-c]quinazolin-13(14H)-one (45). To a solution of
45 (60 mg) and 1,3-dibromo-5,5-dimethylhydantoin in methylene
chloride was added trifluoromethanesulfonic acid. After being stirred
at room temperature for 64 h, the reaction mixture was portioned
between 2 N NaOH solution (50 mL) and EtOAc (40 mL). The aqueous
layer was extracted with EtOAc (3 × 20 mL), and the combined extracts
were washed with brine, dried over Na2SO4, and concentrated. The
crude product was analyzed with LC-MC, and the LC-MC analysis
indicated that the crude contains dibrominated, tribrominated, tetra-
brominated, as well as more highly brominated products, all as isomeric
mixtures.
1287, 1263, 1256, 1232, 1207, 1123, 1034, 832, 812, 765, 751 cm-1
.
1H NMR (CDCl3): δ 1.61 (dd, J ) 14.3 and 8.7 Hz, 1H), 2.08 (dd, J
) 14.3 and 8.7 Hz, 1H), 3.04 (dd, J ) 15.6 and 8.3 Hz, 1H), 3.28 (dd,
J ) 15.6 and 8.3 Hz, 1H), 3.54 (dd, J ) 15.8 and 6.2 Hz, 1H), 3.60 (s,
9
J. AM. CHEM. SOC. VOL. 125, NO. 14, 2003 4251

A R T I C L E S
Liu and McWhorter
Acknowledgment. We dedicate this work to Professor
Yoshito Kishi and congratulate him on receiving the 2001
Tetrahedron Prize for Creativity in Organic Chemistry. We are
grateful to Pharmacia Corp. for supporting a postdoctoral
fellowship for Y.L. We thank Garold L. Bryant and Fusen Han
for the X-ray structure determinations and Chad E. Hadden for
his assistance with the HMBC NMR experiment. We are grateful
to the Analytical Chemistry Department of Pharmacia for
acquiring the IR, UV, HRMS, and combustion analysis data.
We thank Dr. Jed F. Fisher for providing us with useful
references from his personal literature database and for his
interest in our research.
Supporting Information Available: 1H NMR spectra of 4,
9, 10, 11, 12, 13, 14, 5, 15, 16, 17, 20, 21, 22, 23, 24, 25, 26a,
26a/26b, 28, 29, 30, 31, 32, 33, 34, 36, 37, 38, 39, 40, 41, 42,
43, 44, 6, and 45, 13C NMR spectra of 6 and 45 (PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
JA021380M
9
4252 J. AM. CHEM. SOC. VOL. 125, NO. 14, 2003