Aromatic bromination versus oxidation of indolylmalonates by bromine

Article abstract of DOI:10.1021/jo020543m

The reactions of 5-substituted indolylmalonates (2a-e), carrying an electron-withdrawing group at the N(1) position, with bromine in CCl₄ or AcOH are reported. These substrates undergo oxidation in competition with the well-known aromatic bromination. Under the two sets of conditions, with parent indolylmalonate (2a), chemospecific oxidation is observed, whereas with 5-hydroxyindolylmalonate (2c), bromination at the 4- and 6-position is the dominating reaction. Investigation of the products composition of several 5-substituted indolylmalonates revealed the following trend: with a 5-substituted electron-withdrawing group like fluorine, the indolylmalonate undergoes oxidation rather than bromination. In contrast, with a 5-substituted electron-donating group, like a hydroxyl group, the ring bromination occurs preferentially over the oxidation. When the 5-substituent is an alkoxyl group, a significant amount of brominated-oxidized products is obtained. Monitoring the oxidation reaction by mass spectrometry allowed the characterization of the 2-bromoindolylidenemalonate intermediate. A bromonium ion is considered as possible pathway in the formation of this intermediate. The conformation of unsymmetrical methoxyl and benzyloxyl substituents was determined from ¹H NMR spectra, single-crystal X-ray diffraction and ab initio calculations.

Full text of DOI:10.1021/jo020543m

Ar om a tic Br om in a tion ver su s Oxid a tion of In d olylm a lon a tes by
Br om in e
Martha S. Morales-R´ıos, Norma F. Santos-Sa´nchez, Oscar R. Sua´rez-Castillo, and
Pedro J oseph-Nathan*
Departamento de Quı´mica, Centro de Investigacio´n y de Estudios Avanzados del Instituto Polite´cnico
Nacional, Apartado 14-740, Me´xico D. F. 07000, Mexico
pjoseph@nathan.chem.cinvestav.mx
Received August 15, 2002
The reactions of 5-substituted indolylmalonates (2a -e), carrying an electron-withdrawing group
at the N(1) position, with bromine in CCl4 or AcOH are reported. These substrates undergo oxidation
in competition with the well-known aromatic bromination. Under the two sets of conditions, with
parent indolylmalonate (2a ), chemospecific oxidation is observed, whereas with 5-hydroxyindolyl-
malonate (2c), bromination at the 4- and 6-position is the dominating reaction. Investigation of
the products composition of several 5-substituted indolylmalonates revealed the following trend:
with a 5-substituted electron-withdrawing group like fluorine, the indolylmalonate undergoes
oxidation rather than bromination. In contrast, with a 5-substituted electron-donating group, like
a hydroxyl group, the ring bromination occurs preferentially over the oxidation. When the
5-substituent is an alkoxyl group, a significant amount of brominated-oxidized products is obtained.
Monitoring the oxidation reaction by mass spectrometry allowed the characterization of the
2-bromoindolylidenemalonate intermediate. A bromonium ion is considered as possible pathway
in the formation of this intermediate. The conformation of unsymmetrical methoxyl and benzyloxyl
1
substituents was determined from H NMR spectra, single-crystal X-ray diffraction and ab initio
calculations.
In tr od u ction
tion of 3-indolylcyanoacetates with HNO3 or CrO3 yields
stable 2-hydroxyindolenines6 that could be converted to
the corresponding indole alkaloids.5 Although oxidation
of the 2,3 indole double bond, which is essential under
the influence of the substituents in the 1-, 2-, or
3-positions,7a has been carried out with a great variety
of agents, such as bromine,7b,c NBS,7d,e MoO5-HMPA,7f
thallium trinitrate,7g t-BuOCl,7h SO2Cl2,7i lead tetra-
acetate,7j and more recently with m-CPBA,8a CF3CO2H,8b
and OsO4-pyridine,8c this is limited in most cases to the
indol-2- and 3-one formation.
In the past decades, many brominated indole deriva-
tives possessing diverse structural complexity have been
isolated from a variety of marine sources, and as a result,
pharmacological studies using these marine natural
products are increasing in number and scope.1 One of the
most famous brominated indole marine natural product
is tyrian purple isolated from a marine mollusk.2 Other
brominated indoles with important biological activities
are 5-bromo-N,N-dimethyltryptamine, isolated from a
marine sponge,3 and the brominated physostigmine
alkaloids isolated from a cheilostome bryozoan.4
From the point of creating new biologically brominated
active compounds based on indolenine chemistry, we
In the course of our research on 2-hydroxyindolenines,
as intermediates for the synthesis of bioactive brominated
physostigmine alkaloids,5 we have shown that the oxida-
(5) (a) Morales-R´ıos, M. S.; Sua´rez-Castillo, O. R.; J oseph-Nathan,
P. J . Org. Chem. 1999, 64, 1086-1087. (b) Morales-R´ıos, M. S.; Sua´rez-
Castillo, O. R.; Trujillo-Serrato, J . J .; J oseph-Nathan, P. J . Org. Chem.
2001, 66, 1186-1192.
(6) (a) Morales-R´ıos, M. S.; Bucio, M. A.; J oseph-Nathan, P. J .
Heterocycl. Chem. 1993, 30, 953-956. (b) Morales-R´ıos, M. S.; Bucio,
M. A.; J oseph-Nathan, P. Magn. Reson. Chem. 1993, 31, 960-962. (c)
Morales-R´ıos, M. S.; Mart´ınez-Galero, N. X.; Loeza-Coria, M.; J oseph-
Nathan, P. J . Org. Chem. 1995, 60, 6194-6197.
(7) For reviews, see: (a) Karp, G. M. Org. Prep. Proced. Int. 1993,
25, 481-513. (b) Dmitrenko, G. I.; Gross, E. A.; Vice, S. F. Can. J .
Chem., 1980, 58, 808-813. (c) Hino, T.; Nakagawa, M.; Akaboshi, S.
Chem. Pharm. Bull. 1967, 15, 1800-1803. (d) Parrick, J .; Yahya, A.;
Ijaz, S.; Yizun, J . J . Chem. Soc., Perkin Trans. 1 1989, 2009-2015. (e)
Hinman, R. L.; Bauman, C. P. J . Am. Chem. Soc. 1964, 29, 1206-
1215. (f) Chien, C.-S.; Suzuki, T.; Kawasaki, T.; Sakamoto, M. Chem.
Pharm. Bull. 1984, 32, 3945-3951. (g) Ohnuma, T.; Kasuya, H.;
Kimura, Y.; Ban, Y. Heterocycles 1982, 17, 377-380. (h) Walser, A.;
Blount, J . F.; Fryer, R. I. J . Org. Chem. 1973, 38, 3077-3084. (i)
Acheson, R. M.; Prince, R. J .; Proctor, G. J . Chem. Soc., Perkin Trans.
1 1979, 595-598. (j) Hino, T.; Torisawa, Y.; Nakagawa, M. Chem.
Pharm. Bull. 1982, 30, 2349-2356.
† To whom correspondence should be addressed. Phone: (5255) 5747-
7112. Fax: (5255) 5747-7137.
(1) Reviews: (a) Faulkner, D. J . J . Nat. Prod. Rep. 1984, 1, 551-
598. (b) Faulkner, D. J . J . Nat. Prod. Rep. 1986, 3, 1-33. (c) Faulkner,
D. J . J . Nat. Prod. Rep. 1987, 4, 539-576. (d) Faulkner, D. J . J . Nat.
Prod. Rep. 1988, 5, 613-663. (e) Faulkner, D. J . J . Nat. Prod. Rep.
1990, 7, 269-309. (f) Faulkner, D. J . J . Nat. Prod. Rep. 1991, 8, 97-
147. (g) Faulkner, D. J . J . Nat. Prod. Rep. 1992, 9, 323-364. (h) Saxton,
J . E. J . Nat. Prod. Rep. 1994, 11, 493-531. (i) Faulkner, D. J . J . Nat.
Prod. Rep. 1995, 12, 223-270. (j) Ihara, M.; Fukumoto, K. J . Nat. Prod.
Rep. 1995, 12, 277-301. (k) Faulkner, D. J . J . Nat. Prod. Rep. 1996,
13, 75-125. (l) Faulkner, D. J . J . Nat. Prod. Rep. 2001, 18, 1-49.
(2) (a) Bergman, J .; Koch, E.; Pelcman, B. Tetrahedron, 1995, 51,
5631-5642. (b) Butler, A.; Walker, J . V. Chem. Rev. 1993, 93, 1937-
1944.
(3) Djura, P.; Stierle, D. B.; Faulkner, D. J .; Arnold, E.; Clardy, J .
J . Org. Chem. 1980, 45, 1435-1441.
(4) For a review, see: Christophersen, C. Acta Chem. Scand. B 1985,
39, 517-529.
10.1021/jo020543m CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/14/2002
J . Org. Chem. 2003, 68, 305-311
305

Morales-R´ıos et al.
TABLE 1. P r ep a r a tion of In d olylm a lon a tes
competing processes which afforded mixtures with vari-
able composition of bromoindolylmalonates (3-8), in-
dolylidenemalonates (9-12), and bromoindolylidenema-
lonates (13-18). The reactants and the products from our
study are summarized in Scheme 1. The percentages of
products and the reaction conditions are presented in
Table 2.
F lu or in e Su bstitu en t . Depending on the 5-substitu-
ent, either aromatic bromination becomes prominent or
the oxidation occurs to give 2-hydroxy-3-indolylidenema-
lonates predominantly. Reaction of the parent (C5-H)
indolylmalonate 2a and the 5-fluorine derivative 2b, with
2 equiv of Br2 in the nonpolar solvent CCl4 for 2 h,
exhibited complete regioselectivity to give the corre-
sponding 2-hydroxy-3-indolylidenemalonates 9 and 11 in
80 and 16% yield, respectively (entries 1 and 2). In the
latter case, the presence of fluorine as electron-withdraw-
ing substituent retards the oxidation reaction, and un-
reacted 5-fluoroindolylmalonate 2b was recovered in 68%.
However, when in another experiment 2b was reacted
with 2 equiv of Br2 for 12 h, the yield of 11 increased to
66% (entry 3). Bromination of 2a in the polar solvent
AcOH for 2 h leads, in addition to the oxidized products
2-hydroxy- and 2-oxo-3-indolylidenemalonates 9 (44%)
and 10 (20%), to a mixture of 2-bromo- and 2,6-dibromo-
3-indolylmalonates 3 and 4 in a ca. 1:1 ratio, as deter-
a
b
Me2CO3, 2.2 equiv of NaH, rt. Prepared according to the
published procedure.10 c Compound 2c was obtained by demethy-
lation of 2d with BBr3 in 53% yield.
have engaged in the exploration of new synthetic routes
for the formation of 2-hydroxyindolenines. Accordingly,
we are interested in the synthetic utilization of 3-indolyl-
malonates as substrates, since they are expected to show
various competitive reactivities attributable to both the
benzene and the heterocyclic ring, when reacted with
bromine. Thus, in indoles, a strong deactivating sub-
stituent at the pyrrole ring or a strong activating sub-
stituent at the benzene ring has been recognized to
increase the regiospecificity of the later to electrophilic
substitution.9
1
mined by H NMR spectral integration, in 18% global
yield (entry 4). The same Rf value for 3 and 4 precluded
isolation of 4. Under the above conditions, the 5-fluorine
derivative 2b was transformed only into the oxidized
products 5-fluoro-2-hydroxy- 11 (31%) and 5-fluoro-2-oxo-
3-indolylidenemalonates 12 (46%) (entry 6). In a subse-
quent reaction with 1 equiv of Br2, 11 was transformed
into the oxoindolylidenemalonate 12 in 53% yield (entry
7).
In this work, we have investigated the effects of both
the electronic and the steric effects on the reaction of
5-substituted 1-carbomethoxy-3-indolylmalonates (2a -
e) with bromine in order to rationalize its mechanism
and to further demonstrate their synthetic availability
as building blocks toward complicated naturally occurring
and modified indole derivatives.
Oxygen a ted Activa tin g Su bstitu en ts. In the pres-
ence of ring-A oxygenated activating groups, ring bro-
mination should be facilitated over the oxidation. Reac-
tion of 2c, with 1 equiv of Br2 in CCl4 for 2 h, revealed
that ortho monobromination at C(4) was the favored
initial reaction, leading to 4-bromo-5-hydroxy-3-indolyl-
malonate 5 in 58% yield, together with some 4,6-dibromo-
5-hydroxy-3-indolylmalonate 6 (6%) and traces of 4-bromo-
5-hydroxy 3-indolylidenemalonate 13 (entry 8). Compound
13, of easy decomposition, could be characterized only by
1H NMR and EIMS data. When, in another experiment,
2c was reacted with 2 equiv of Br2 in CCl4 for 2 h the
yield of 6 (21%) increased at the expense of 5 (45%) (entry
9). Finally, 6 was obtained as the major product (49%)
upon reaction with 2 equiv of Br2 in CCl4 for 5 h. Small
amounts of the 4-brominated regioisomer 5 (13%) were
also observed (entry 10). In AcOH as solvent, the global
yields of brominated products 5 and 6 in entries 11 and
12 were almost the same (57 and 56%, respectively), but
the ratio of 5 to 6 decreased in time. These facts indicate
that the 4,6-dibromoindolylmalonate 6 was formed by
further bromination of the corresponding 4-bromoindole
5. Compound 6 was further reacted with 1 equiv of Br2
in AcOH for 0.5 h to afford the 4,6-dibromated 2-hy-
droxyindolylidenemalonate 18 in 30% yield (entry 13).
By increasing the reaction time to 2 h, the yield of 18
decreases to 17%. The 4-bromo- and 4,6-dibromoindolyl-
malonates 5 and 6 were isolated and then identified by
1H NMR and mass spectroscopy.
Resu lts
5-Substituted
1-carbomethoxyl-3-indolylmalonates
2a ,b,d ,e were prepared from the corresponding methyl
3-indolyl acetates 1a ,b,d ,e by Claisen condensation with
dimethyl carbonate in the presence of sodium hydride in
good yields (70-88%) as shown in Table 1. The starting
materials 1 were previously synthesized by hydrolysis
and esterification of the corresponding 3-indoleacetoni-
trile.10 The demethylation of 2d was performed with BBr3
to furnish the desired product 2c in moderate yield (see
Table 1).
When indolylmalonates 2a -e were stirred with 2 equiv
of Br2 in both CCl4 and AcOH at room temperature,
aromatic bromination and oxidation were found to be
(8) (a) Bourlot, A. S.; Desarbre, E.; Me´rour, J . Y. Synthesis, 1994,
411-416. (b) Gu¨ler, R.; Borschberg, H.-J . Tetrahedron Lett. 1994, 35(6),
865-868. (c) Peterson, A. C.; Cook, J . M. J . Org. Chem. 1995, 60, 120-
129.
(9) Brennan, M. R.; Erickson, K. L.; Szmalc, F. S.; Tansey, M. J .;
Thornton, J . M. Heterocycles 1986, 24, 2879-2885.
(10) Rozhkov, V. S.; Smushkevich, Y. I.; Suvorov, N. N. Khim.
Geterotsikl. Soedin. 1980, 55-58; Chem. Abstr. 1980, 93, 8124j.
306 J . Org. Chem., Vol. 68, No. 2, 2003

Aromatic Bromination vs Oxidation of Indolylmalonates
SCHEME 1. Rea ction of In d olylm a lon es w ith Br om in e
TABLE 2. P r od u cts a n d Yield s (%)a in th e Rea ction of In d olylm a lon a tes 2 a n d 6 a n d In d olylid en em a lon a te 11 w ith
Br om in eb
solvent
ring brominatione-g
entry
CCl4
AcOH
equiv of Br2
time (h)
ring brominationc-f
oxidation
9 (80)
11 (16)
11 (66)
9 (44) + 10 (20)
9 (70) + 10 (2)
11 (31) + 12 (46)
12 (53)
and oxidation
1
2
3
2a
2
2
2
2
1
2
1
1
2
2
2
2
1
2
2
3
2
2
2
2
12
2
2
5
5
2
2
5
2
5
0.5
3
5
6
2
5
2bh
2b
4
5
6
7
2a
2a i
2b
3 (9)c + 4 (9)d
3 (11)c
11
8
9
2c
2c
2c
5 (58)e + 6 (6)f
5 (45)e + 6 (21)f
5 (13)e + 6 (49)f
5 (27)e + 6 (30)f
5 (14)e + 6 (42)f
13 (traces)e
13 (traces)e
13 (traces)e
13 (9)e
10
11
12
13
14
15
16
17
18
2c
2c
6
13 (7)e
18 (30)f
2d
2e
7 (46)d
14 (27)e + 15 (25)g
15 (25)g
2d
2d
7 (70)d
-
14 (52)e + 15 (27)g
5 (57)d + 8 (26)d
8 (56)d
2e
16 (17)e + 17 (23)g
a
b
d
Percentages of isolated reaction products. Reactions carried out at room temperature. c Ring bromination at C(2). Ring bromination
at C(2,6). e Ring bromination at C(4). f Ring bromination at C(4,6). g Ring bromination at C(6). Unreacted starting material was recovered
in 68% yield. Unreacted starting material was recovered in 10% yield.
h
i
In an extension of this investigation, we studied the
unsymmetrical methoxyl and benzyloxyl substituents.
When 5-methoxyindolylmalonate 2d was stirred with 2
equiv of Br2 in CCl4 for 3 h, electrophilic attack at the
C(4) position afforded the 4-bromoindole 7 (46%) as
the major product. An interesting observation is that, in
this case, besides the expected 4-bromo-2-hydroxy-3-
indolylidenemalonate 14 (27%), the 6-brominated regio-
isomer 15 (25%) was also formed (entry 14). On the other
hand, treatment of 2d with 2 equiv of Br2 in AcOH for 5
h afforded 7 (70%) and only the regioisomer 15 (25%)
(entry 15). One noticeable feature of this conversion is
that when the reaction time is extended from 2 to 5 h in
the presence of 3 equiv of Br2 (entry 16), the 4- and
6-brominated indolylidenemalonates 14 (52%) and 15
(27%) were formed as the sole products. In all sets of
conditions, not even traces of 6-brominated indole were
found.
J . Org. Chem, Vol. 68, No. 2, 2003 307

Morales-R´ıos et al.
When 5-benzyloxyindole 2e was subjected to bromina-
tion in CCl4 for 2 h, the 5-benzyloxy-4-bromo-3-indolyl-
malonate 8 was isolated in only 26% yield. In addition,
unexpected debenzylated 4-bromo-5-hydroxyindole de-
rivative 5 (57%) was also obtained (entry 17). Bromina-
tion of 2e in AcOH for 5 h provided 4-bromoindole
derivative 8 (56%) together with 4-bromo- and 6-bromo-
3-indolylidenemalonates 16 (17%) and 17 (23%). Under
these reaction conditions, not even traces of debenzylated
derivative 5 were found (entry 18).
Discu ssion
Rea ctivity. At first, a number of reaction variables
were investigated, e.g., solvent, molar ratio of bromine
and reaction time. Although it is know that the use of
polar solvents such as AcOH enhances the reactivity of
bromine to electrophilic bromination,11 except for 2a and
2b, the conversions of 2c-e (Table 2) were slightly
dependent on the solvent effect. For the compounds
studied, the regiochemistry of the bromination was
mainly dependent on the electronic effects and steric
hindrance of the substituent in the benzene ring. The
oxidation reaction at the pyrrole moiety of indolylma-
lonates 2a and 2b was not surprising since the N(1)
protecting group deactivated the indole core and permit-
ted the oxidation as the principal pathway.6 This reaction
is slowed with the electron-withdrawing 5-fluorine sub-
stituent.
In the case of 2c-e, two contrasting factors were
involved in the electrophilic vs oxidation process. The
presence of an electron-withdrawing group at the N(1)
position deactivates the indole nucleus to electrophilic
attack. However, the oxygenated activating groups (OH,
OMe, OBn) are expected to promote the electrophilic
bromination on the benzene moiety. As can be seen in
Table 2, the hydroxyl group in 2c activates the aromatic
ring for electrophilic bromination at the ortho positions
with high chemospecificity, only a small amount of a
brominated-oxidized product was detected. The bromi-
nation initially took place at the C(4) position to give
regioselectively, by precise optimization of reaction condi-
tions, the 4-bromoindole derivative 5. Further bromina-
tion at the C(6) position can be easily effected by
increasing the molar ratio of bromine and the reaction
time.
F IGURE 1. Positive NOEs of different magnitude which occur
at H4 and H6 upon irradiation of the 5-methoxyl group of 2d .
tions, the presence of a methoxyl group promotes oxida-
tion of the indole double bond rather than a second ring
bromination, so that ring dibromination is completely
overruled in 2d . Likewise, the reaction of 5-benzyloxy-
indolylmalonate 2e, only gave the monobrominated prod-
ucts.
The different reactivity with which the C(4) and C(6)
positions in 2d and 2e undergo electrophilic bromination
is a consequence of two factors: the unequal π-electron
density at the positions ortho to methoxyl or benzyloxyl
substituents, and the steric interactions developed upon
electrophilic attack between the alkoxyl group and the
approaching bromine. The conformational preference of
the unsymmetrical oxygenated groups,12 derived from
NMR studies, ab initio quantum chemistry (HF/3-21G*)
and X-ray diffraction analysis, are all interpreted as
consistent with a conformer in which the 5-O-alkyl group
lies predominantly s-cis to H4. Thus, in DMSO-d6 positive
NOEs of different magnitude occur at the H4 (18%) and
H6 (8%) signals upon irradiation of the 5-methoxyl group
of 2d (Figure 1). Ab initio calculations of the conformer
stabilities for 2d and 2e predict the s-cis to H4 form to
be 1.38 and 1.28 kcal/mol, respectively, lower in energy
than the s-trans form, corresponding to 91% and 90%
abundance of the s-cis to H4 form, respectively, at 298
K. The X-ray crystal structure for 2e13 is shown in Figure
2. The C4-C5-O5-C15 torsion angle value of -5.3° is
in agreement with the NMR results and theoretical
predictions. The structures and conformation of the
4-bromo-5-methoxyindole derivative 7,14 and the 5-hy-
droxylated compounds 2c15 and 516 were also determined
by X-ray diffraction studies. In these cases the C4-C5-
O5-C15 torsion angle value is 170.3° for 7, whereas for
With 5-methoxyindolylmalonate 2d , a remarkable
feature becomes apparent: although electronically, the
methoxyl group is expected to influence the product
formation in a similar way than the hydroxyl group in
2c, the reactivity of 2d shows a markedly difference. In
2d , ring bromination and oxidation occur under the
standard conditions (entries 14 and 15), monobrominated
products at C(4) 7 and 14 and at C(6) 15 were obtained
in ca. 3:1 ratio. In addition, the steric effect of the
methoxyl group is important enough to prevent the
formation of 4,6-dibrominated products despite an excess
of molar ratio of bromine (entry 16). Under these condi-
(12) (a) Kruse, L. I.; DeBrosse, C. W.; Kruse, C. H. J . Am. Chem.
Soc. 1985, 107, 5435-5442. (b) Ernst, L. Angew. Chem. 1976, 15, 303-
304. (c) J oseph-Nathan, P.; Garc´ıa-Mart´ınez, C.; Morales-R´ıos, M. S.
Magn. Reson. Chem. 1990, 28, 311-314.
(13) Colorless crystals of 2e (C22H21O7N) were grown from EtOAc/
hexane. Data collection was conducted at 293 K on a triclinic crystal:
P1(bar); a ) 9.8474(5) Å, b ) 10.3596(5) Å, c ) 11.3164(5) Å, R )
78.055(1)°, â ) 86.923(1)°, γ ) 65.457(1)°; V ) 1026.72(9) Å3, Z
) 2; R1 ) 4.5%, wR2 ) 11.9%, GOF ) 1.038. CCDC20 deposition no.
194861.
(14) Colorless crystals of 7 (C16H16O7NBr) were grown from EtOAc/
hexane. Data collection was conducted at 293 K on a monoclinic
crystal: C2; a ) 12.111(2) Å, b ) 7.048(1) Å, c ) 20.932(3) Å, â )
102.899(3)°; V ) 1742.6(5) Å3, Z ) 4; R1 ) 5.7%, wR2 ) 15.6%, GOF )
1.073. CCDC20 deposition no. 194863.
(11) (a) Kruse, L. I.; Meyer, M. D. J . Org. Chem. 1984, 49, 4761-
4768. (b) Tani, M.; Ikegami, H.; Tashiro, M.; Hiura, T.; Tsukioka, H.;
Kaneko, C.; Notoya, T.; Shimizu, M.; Uchida, M.; Aida, Y.; Yokoyama,
Y.; Murakami, Y. Heterocycles 1992, 34, 2349-2362. (c) Somei, M.;
Fukui, Y.; Hasegawa, M.; Oshikiri, N.; Hayashi, T. Heterocycles 2000,
53, 1725-1736.
308 J . Org. Chem., Vol. 68, No. 2, 2003

Aromatic Bromination vs Oxidation of Indolylmalonates
F IGURE 3. EIMS monitoring of the reaction of 2a with Br2
in CCl4 at (a) t ) 0, (b) t ) 1 h, and (c) t ) 2 h.
SCHEME 2
F IGUR E 2. X-ray diffraction (top) and ab initio computed
structure (bottom) of 2e.
2c and 5 the C4-C5-O5-H5 torsion angle values are
-11.4° and -165.8°, respectively (see the Supporting
Information).
Mech a n ist ic st u d ies. A reasonable mechanism for
the formation of 2-hydroxyindolenines from 3-indolylma-
lonates is outlined in Scheme 2. The first step in this
proposal involves an electrophilic addition of Br2 to the
C(2)dC(3) double bond to form perhaps a bromonium ion
intermediate 19, followed by H8-abstraction generating
the labile intermediate 2-bromoindolenine 20, which is
further hydrolyzed during the aqueous workup procedure
to afford the corresponding 2-hydroxyindolenines 9, 11,
and 13-18. To test this hypothesis, the conversion of 2a
was followed by EI mass spectrometry. Spectra were
taken immediately after the addition of Br2 (2 equiv) to
a solution of 2a in CCl4 and from then on every 30 min.
The new diagnostic peaks, M+ and (M + 2)+ at 383 and
385 amu, respectively, which grew in during the course
of the reaction, agree very well with those of the expected
brominated indolenine 20 (Figure 3). No other products
were identifiable until 2 h. Analysis by TLC (silica gel,
3:7 EtOAc/hexane) of this crude mixture revealed that
2a was consumed and that 9 (Rf 0.15) is present together
with a higher Rf value (0.47) intermediate 20 (estimated
75%) which transforms, on standing for several hours on
the silica gel coated aluminum sheet, to 9. In addition,
when 2d was reacted with Br2 (2 equiv) at room temper-
ature in CCl4, MS monitoring of the reaction showed that
two bromine atoms were consecutively incorporated into
2d . The intermediate monobrominated product gradually
disappeared from the reaction mixture, and the sole
product containing two bromine atoms (according to MS
data) was observed. These results provide strong support
for a scenario where the oxidation reactions with Br2
proceed via a 2-bromoindolenine and subsequent hy-
drolysis.
(15) Colorless crystals of 2c (C15H15O7N) were grown from EtOAc/
hexane. Data collection was conducted at 293 K on a triclinic crystal:
P1(bar); a ) 7.9296(9) Å, b ) 8.5864(9) Å, c ) 11.618(1) Å, R ) 81.308-
(2)°, â ) 78.344(3)°, γ ) 77.467(3)°; V ) 751.5(1) Å3, Z ) 2; R1 ) 7.1%,
wR2 ) 17.1%, GOF ) 0.922. CCDC20 deposition no. 194860.
On the other hand, analysis of substituent effects on
the product compositions (Table 2) revealed that a further
oxidation of 2-hydroxy-3-indolylidenemalonates to 2-oxo
derivatives is suppressed when increasing the electron-
(16) Colorless crystals of 5 (C15H14O7NBr) were grown from EtOAc/
hexane. Data collection was conducted at 293 K on a triclinic crystal:
P1(bar); a ) 7.916(5) Å, b ) 9.289(5) Å, c ) 12.133(5) Å, R ) 76.908-
(5)°, â ) 72.999(5)°, γ ) 85.391(5)°; V ) 830.9(8) Å3, Z ) 2; R1 ) 7.2%,
wR2 ) 16.6%, GOF ) 0.987. CCDC20 deposition no. 194862.
J . Org. Chem, Vol. 68, No. 2, 2003 309

Morales-R´ıos et al.
Gen er a l P r oced u r e for th e P r ep a r a tion of In d olyl
SCHEME 3
Aceta tes 1b,d ,e. Compounds 1b, 1d , and 1e were prepared
in a manner similar to that previously described for 1a .10
A
mixture of 7.8 mmol of the appropriate acetonitrylindole19 in
20 mL of aqueous 20% KOH was refluxed for 5 h, and after
cooling, the reaction was made acid with 10 N aqueous HCl.
The resulting suspension was vacuum filtered, and the pre-
cipitate was washed with water. The residue was purified by
crystallization (EtOAc). All indolylacetic acids were character-
ized by NMR affording spectral data in agreement with their
structure.
A solution of the corresponding indolylacetic acid in anhy-
drous MeOH (25 mL) was stirred with 10 N HCl (0.1 mL) at
reflux for 2 h. The mixture was purified by flash column
chromatography on silica gel (EtOAc/hexane, 1:4) or Kugelrohr
distillation (110-122 °C, 0.5 mmHg) to afford a solid in overall
yields of 63-66%.
Meth yl (5-flu or o-1H-in d ole-3-yl)a ceta te (1b): slightly
pink solid; mp 71-73 °C on standing; Rf 0.20 (EtOAc/hexane
1:4); IR (CHCl3) νmax 3042, 1734, 1488, 1176 cm-1 1H NMR
;
(DMSO-d6) δ 11.05 (1H, br s, NH), 7.34 (1H, dd, J ) 9.0, 4.7
Hz, H7), 7.32 (1H, br s, H2), 7.22 (1H, dd, J ) 10.1, 2.5 Hz,
H4), 6.91 (1H, td, J ) 9.0, 2.5 Hz, H6), 3.72 (2H, s, H8), 3.60
(3H, s, CO2Me); 13C NMR (DMSO-d6) δ 171.9 (CdO), 156.8 (d,
J ) 231.2 Hz, C5), 132.8 (C7a), 127.4 (d, J ) 10.1 Hz, C3a),
126.2 (C2), 112.4 (d, J ) 9.8 Hz, C7), 109.2 (d, J ) 25.9 Hz,
C6), 107.3 (d, J ) 4.9 Hz, C3), 103.2 (d, J ) 23.3 Hz, C4), 51.5
(OMe), 30.4 (C8); EIMS m/z 207 (M+, 35), 148 (100), 101 (11);
HRMS (FAB) m/z 207.0703 (M+, C11H10NO2F requires
207.0696).
donating character of the 5-substituent. On this basis,
the formation of 2-oxo-3-indolylidenemalonates 10 and
12 by oxidation of 9 and 11, respectively, with bromine
in the polar AcOH solvent is assumed to occur by removal
of the hemiaminalic proton form C(2) and hydride
transfer from oxygen (path a), rather than by hydride
transfer from C(2) and proton removal from oxygen17
(path b), as described in Scheme 3. In CCl4, the oxidation
did not proceed at all. A reaction mechanism involving
the initial tautomerization of the exocyclic 3(8)-double
bond to the 2,3-endocyclic position is ruled out, since
tretment of 11 with catalytic amounts of H2SO4 in AcOD-
Meth yl (5-m eth oxy-1H-in d ole-3-yl)a ceta te (1d ): slightly
yellow solid; mp 70-71 °C on standing; Rf 0.20 (EtOAc/hexane
1:4); IR (CHCl3) νmax 3012, 1732, 1220, 1058 cm-1 1H NMR
;
(DMSO-d6) δ 10.79 (1H, br s, NH), 7.26 (1H, d, J ) 8.8 Hz,
H7), 7.21 (1H, d, J ) 2.3 Hz, H2), 6.99 (1H, d, J ) 2.4 Hz,
H4), 6.75 (1H, dd, J ) 8.8, 2.4 Hz, H6), 3.75 (3H, s, OMe),
3.72 (2H, s, H8), 3.61 (3H, s, CO2Me); 13C NMR (DMSO-d6) δ
172.0 (CdO), 153.1 (C5), 131.2 (C7a), 127.4 (C3a), 124.6 (C2),
112.0 (C7), 111.1 (C6), 106.7 (C3), 100.3 (C4), 55.3 (OMe), 51.4
(OMe ester), 30.6 (C8); EIMS m/z 219 (M+, 72), 160 (100), 145
(18); HRMS (FAB) m/z 219.0895 (M+, C12H13NO3 requires
219.0895).
1
d3 for 10 h did not induced any change in its H NMR
spectrum.
In summary, a novel straightforward strategy for
highly functionalized 2-hydroxyindolenines was devel-
oped based on indolylmalonates that employs very mild
reaction conditions. This methodology permits entry into
versatile indole building blocks for the syntheses of indole
alkaloids and nonnatural analogues.
Meth yl (5-ben zyloxy-1H-in dole-3-yl)acetate (1e): slightly
pink solid; mp 41-43 °C on standing; Rf 0.20 (EtOAc/hexane
1:4); IR (CHCl3) νmax 3070, 1712, 1626, 1248 cm-1 1H NMR
;
(DMSO-d6) δ 10.79 (1H, br s, NH), 7.47-7.30 (5H, m, Ar), 7.24
(1H, d, J ) 8.8 Hz, H7), 7.19 (1H, d, J ) 2.4 Hz, H2), 7.07
(1H, d, J ) 2.4 Hz, H4), 6.80 (1H, dd, J ) 8.8, 2.4 Hz, H6),
5.06 (2H, s, OCH2), 3.69 (2H, d, J ) 0.6 Hz, H8), 3.57 (3H, s,
OMe); 13C NMR (DMSO-d6) δ 172.0 (CdO), 152.2 (C5), 137.8
(Ci), 131.4 (C7a), 128.3 (Cm), 127.6 (Co), 127.4 (Cp, C3a), 124.8
(C2), 112.1 (C7), 111.8 (C6), 106.7 (C3), 102.0 (C4), 69.8
(OCH2), 51.5 (OMe), 30.6 (C8); EIMS m/z 295 (M+, 84), 204
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. Ana-
lytical thin-layer chromatography (TLC) was performed on
silica gel 60 F254 coated aluminum sheets (0.25 mm thickness)
with a fluorescent indicator. Visualization was accomplished
with UV light (254 nm). Flash chromatography was performed
using silica gel 60 (230-400 mesh). IR spectra were obtained
using a FT spectrophotometer. NMR spectra were recorded
(100), 146 (56), 91 (43); HRMS (FAB) m/z 295.1213 (M+, C18H17
-
NO3 requires 295.1208).
Gen er a l P r oced u r e for th e P r ep a r a tion of Ma lon a tes
2. Compounds 2b, 2d , and 2e were prepared in a manner
similar to that previously described for 2a .10 To a solution of
the appropriate methyl 3-indolyl acetate 1 (4.4 mmol) in Me2-
CO3 (30 mL) under argon at rt was added NaH (0.27 g, 11.1
mmol). The mixture was stirred at rt until TLC analysis
showed complete loss of starting material 18 h for 2b, 1 h for
2d , and 16 h for 2e. After brine (60 mL) was added to the
reaction mixture, the organic layer was separated, dried over
Na2SO4, and evaporated. The resultant crude product was
purified by flash chromatography on silica gel.
1
on spectrometers operating at 300 and 75 MHz for H and 13C,
respectively. Chemical shifts are reported in ppm downfield
from tetramethylsilane. NOE enhancements were determined
1
from 1D difference NOE H NMR spectra obtained by subtrac-
tion of two spectra acquired at identical conditions except for
irradiation frequency. LREIMS and HRMS were measured
using direct inlet spectrometers. All the commercial grade
reagents were used without further purification. Calculations
for the ab initio HF/3-21G*-optimized structures were per-
formed using PC-based programs.18
(19) (a) Stoll, A.; Troxler, F.; Peyer, J .; Hofmann, A. Helv. Chim.
Acta 1955, 38, 1452-1472. (b) US 4283410.
(20) The authors have deposited atomic coordinates for the structure
with the Cambridge Crystallographic Data Center. The coordinates
can be obtained, on request, from the Director, Crystallographic Data
Center 12 Union Road, Cambridge CB2 1Z, U.K.
(17) Swain, C. G.; Wiles, R. A.; Bader, R. F. W. J . Am. Chem. Soc.
1961, 83, 1945-1950.
(18) Hehre, W. J .; Deppmeier, B. J .; Klunzinger, P. E. A PC Spartan
Pro Tutorial; Wavefunction, Inc.: Irvine, CA, 1999.
310 J . Org. Chem., Vol. 68, No. 2, 2003

Aromatic Bromination vs Oxidation of Indolylmalonates
Dim eth yl 2-(1-Ca r bom eth oxy-1H-in d ol-3-yl)m a lon a te
(2a ). Prepared from 1a as colorless crystals (1.07 g, 81%): mp
109-111 °C (EtOAc/hexane) [lit.10 108-110 °C (MeOH)]; Rf
0.40 (EtOAc/hexane 3:7); IR (CHCl3) νmax 3026, 1741, 1448
cm-1; 1H NMR (DMSO-d6) δ 8.12 (1H, d, J ) 8.2 Hz, H7), 7.81
(1H, s, H2), 7.64 (1H, dd, J ) 7.8, 1.2 Hz, H4), 7.38 (1H, td, J
) 7.8, 1.2 Hz, H6), 5.36 (1H, s, H8), 4.00 (3H, s NCO2Me), 3.71
(6H, s, 2 CO2Me);13C NMR (DMSO-d6) δ 168.0 (2 CO2Me), 150.6
(NCO2Me), 134.6 (C7a), 128.7 (C3a), 125.1 (C2), 124.8 (C6),
123.0 (C5), 114.6 (C7), 113.1 (C3), 120.1 (C4), 54.2 (NCO2Me),
52.4 (2 CO2Me), 48.2 (C8); EIMS m/z 305 (M+, 61), 246 (100),
174 (15); HRMS (FAB) m/z 305.0894 (M+, C15H15NO6 requires
305.0899).
411 (M+, 95), 320 (100), 91 (50); HRMS (FAB) m/z 411.1304
(M+, C22H21NO7 requires 411.1318).
Dim eth yl 2-(1-Car bom eth oxy-5-h ydr oxy-1H-in dol-3-yl)-
m a lon a te (2c). To a solution of malonate 2d (0.21 g, 0.6 mmol)
in CHCl3 (13 mL) under argon at 0 °C was added BBr3 (2.1
mL of a 1 M solution in CH2Cl2). The reaction mixture was
stirred for 2.5 h at this temperature and quenched by adding
water (5 mL). The aqueous phase was extracted with CHCl3
(3 × 30 mL), and the combined organic layers were washed
with brine (40 mL), dried over Na2SO4, and evaporated. The
resultant crude product was purified by flash chromatography
on silica gel (EtOAc/hexane 4:1) to give 2c as colorless crystals
(0.1 g, 53%): mp 172-173 °C (EtOAc/hexane); Rf 0.08 (EtOAc/
hexane 1:4); IR (CHCl3) νmax 3510, 3020, 1740, 1226 cm-1; 1H
NMR (DMSO-d6) δ 9.32 (1H, s, OH), 7.89 (1H, d, J ) 8.8 Hz,
H7), 7.72 (1H, s, H2), 6.96 (1H, d, J ) 2.3 Hz, H4), 6.84 (1H,
dd, J ) 8.8, 2.3 Hz, H6), 5.25 (1H, s, H8), 3.97 (3H, s NCO2Me),
3.71 (6H, s, 2 CO2Me); 13C NMR (DMSO-d6) δ 167.9 (CO2Me),
153.4 (C5), 150.6 (NCO2Me), 129.8 (C3a), 128.4 (C7a), 125.5
(C2), 115.2 (C7), 113.9 (C6), 112.8 (C3), 104.9 (C4), 54.0
(NCO2Me), 52.7 (CO2Me), 48.5 (C8); EIMS m/z 321 (M+, 44),
Dim eth yl 2-(1-Ca r bom eth oxy-5-flu or o-1H-in d ol-3-yl)-
m a lon a te (2b). Prepared from 1b as yellow solid (1.0 g,
70%): mp 71-73 °C (CH2Cl2/hexane); Rf 0.32 (EtOAc/hexane
1:4); IR (CHCl3) νmax 3020, 1738, 1266, 1196 cm-1 1H NMR
;
(DMSO-d6) δ 8.11 (1H, dd, J ) 9.4, 4.7 Hz, H7), 7.87 (1H, s,
H2), 7.45 (1H, dd, J ) 9.4, 2.6 Hz, H4), 7.24 (1H, td, J ) 9.4,
2.6 Hz, H6), 5.39 (1H, s, H8), 4.00 (3H, s NCO2Me), 3.79 (6H,
s, 2 CO2Me);13C NMR (DMSO-d6) δ 167.9 (2 CO2Me), 158.5 (d,
J ) 237.3 Hz, C5), 150.4 (NCO2Me), 131.2 (C7a), 129.9 (d, J
) 10.3 Hz, C3a), 127.0 (d, J ) 8.6 Hz, C2), 116.0 (d, J ) 9.4
Hz, C7), 112.9 (d, J ) 4.3 Hz, C3), 112.6 (d, J ) 25.5 Hz, C6),
105.9 (d, J ) 24.6 Hz, C4), 54.4 (NCO2Me), 52.9 (2 CO2Me),
48.2 (C8); EIMS m/z 323 (M+, 47), 264 (100), 192 (17); HRMS
(FAB) m/z 323.0791 (M+, C15H14NO6F requires 323.0805).
Dim eth yl 2-(1-Ca r bom eth oxy-5-m eth oxy-1H-in d ol-3-
yl)m a lon a te (2d ). Prepared from 1d as colorless crystals (1.1
g, 76%): mp 145-146 °C (EtOAc); Rf 0.24 (EtOAc/hexane 1:4);
IR (CHCl3) νmax 3014, 2838, 1738, 1264 cm-1; 1H NMR (DMSO-
d6) δ 7.98 (1H, d, J ) 9.0 Hz, H7), 7.75 (1H, s, H2), 7.18 (1H,
d, J ) 2.6 Hz, H4), 6.99 (1H, dd, J ) 9.0, 2.6 Hz, H6), 5.35
(1H, s, H8), 3.98 (3H, s NCO2Me), 3.79 (3H, s, OMe), 3.72 (6H,
s, 2 CO2Me); 13C NMR (DMSO-d6) δ 168.0 (2 CO2Me), 155.6
(C5), 150.5 (NCO2Me), 129.8 (C3a), 129.1 (C7a), 125.5 (C2),
115.3 (C7), 113.3 (C6), 113.0 (C3), 102.9 (C4), 55.4 (OMe), 54.1
(NCO2Me), 52.7 (2 CO2Me), 48.2 (C8); EIMS m/z 335 (M+, 68),
262 (100), 190 (9); HRMS (FAB) m/z 321.0856 (M+, C15H15
-
NO7 requires 321.0849).
Gen er a l P r oced u r e for Br om in a tion of Ma lon a tes. To
a solution of the appropriate malonate 2a -e (0.64 mmol) in
CCl4 (45 mL) or AcOH (30 mL) was added Br2 (1.28 mmol,
0.066 mL) at rt at once, and the resulting mixture was stirred
at this temperature during the time indicated in Table 2. After
water (15 mL) was added to the reaction mixture, the stirring
was continued at rt for 20 min. The aqueous phase was
extracted with CHCl3 or EtOAc (2 × 80 mL), and the combined
organic layers were washed with brine (3 × 40 mL), and
evaporated. The residue was dissolved in aq 20% THF (70 mL)
and refluxed for 2 h. THF was then removed under reduced
pressure and the residue was extracted with EtOAc (2 × 50
mL), washed with brine, dried over Na2SO4, and evaporated
to afford a yellow oil. Flash chromatography on silica gel
(EtOAc/hexane) afforded the products indicated in Scheme 1.
Individual reaction yields are given in Table 2.
276 (100), 217 (6); HRMS (FAB) m/z 335.1021 (M+, C16H17
-
NO7 requires 335.1005).
Dim eth yl 2-(5-Ben zyloxy-1-ca r bom eth oxy-1H-in d ol-3-
yl)m a lon a te (2e). Prepared from 1e as yellow crystals (1.6
g, 88%): mp 109-110 °C (Et2O); Rf 0.24 (EtOAc/hexane 1:4);
IR (CHCl3) νmax 3016, 1738, 1264, 1022 cm-1; 1H NMR (DMSO-
d6) δ 7.98 (1H, d, J ) 9.1 Hz, H7), 7.73 (1H, s, H2), 7.48-7.32
(5H, m, Ar), 7.27 (1H, d, J ) 2.4 Hz, H4), 7.06 (1H, dd, J )
9.1, 2.4 Hz, H6), 5.32 (1H, s, H8), 5.11 (2H, br s, OCH2), 3.96
(3H, s, NCO2Me), 3.68 (6H, s, 2 CO2Me); 13C NMR (DMSO-d6)
δ 168.1 (2 CO2Me), 154.7 (C5), 150.6 (NCO2Me), 137.1 (Ci),
129.8 (C3a), 129.3 (C7a), 128.4 (Cm), 127.8 (Cp), 127.7 (Co),
125.7 (C2), 115.4 (C7), 114.0 (C6), 113.0 (C3), 104.3 (C4), 69.7
(OCH2), 54.2 (NCO2Me), 52.8 (2 CO2Me), 48.2 (C8); EIMS m/z
Ack n ow led gm en t . This research was partially
suported by CONACYT (Mexico). N.F.S.-S. gratefully
acknowledges CONACYT for a doctoral fellowship. We
thank I. Q. Luis Velasco Ibarra (Instituto de Qu´ımica,
UNAM) for recording the HRMS.
Su p p or tin g In for m a tion Ava ila ble: X-ray structure
1
data, H and 13C spectra, computational data, and character-
ization data for compounds 3-18. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O020543M
J . Org. Chem, Vol. 68, No. 2, 2003 311