Regiospecific Bromination of 3-Methylindoles with NBS and Its Application to the Concise Synthesis of Optically Active Unusual Tryptophans Present in Marine Cyclic Peptides

Article abstract of DOI:10.1021/jo971067g

A regiospecific bromination of substituted 3-methylindoles at either the C(3) alkyl moiety or the C(2) position was achieved via a free radical bromination or electrophilic process, respectively. The regiospecificity of the bromination could be controlled by variation of both the substituent and the N(1) protecting group on the indole ring. In addition, enantiospecific syntheses of 5-methoxytryptophan (20) and 5-hydroxy-6-chlorotryptophan (21c) as well as concise syntheses of optically active 2-bromotryptophan ethyl esters 26a,b or their substituted derivatives in three steps from bifunctional dibromoindoles were achieved via the above regiospecific process.

Full text of DOI:10.1021/jo971067g

J . Org. Chem. 1997, 62, 7447-7456
7447
Regiosp ecific Br om in a tion of 3-Meth ylin d oles w ith NBS a n d Its
Ap p lica tion to th e Con cise Syn th esis of Op tica lly Active Un u su a l
Tr yp top h a n s P r esen t in Ma r in e Cyclic P ep tid es1
Ruiyan Liu, Puwen Zhang, Tong Gan, and J ames M. Cook*
Department of Chemistry, University of WisconsinsMilwaukee, Milwaukee, Wisconsin 53211
Received J une 12, 1997X
A regiospecific bromination of substituted 3-methylindoles at either the C(3) alkyl moiety or the
C(2) position was achieved via a free radical bromination or electrophilic process, respectively. The
regiospecificity of the bromination could be controlled by variation of both the substituent and the
N(1) protecting group on the indole ring. In addition, enantiospecific syntheses of 5-methoxytryp-
tophan (20) and 5-hydroxy-6-chlorotryptophan (21c) as well as concise syntheses of optically active
2-bromotryptophan ethyl esters 26a ,b or their substituted derivatives in three steps from bifunc-
tional dibromoindoles were achieved via the above regiospecific process.
Peptides comprise one of the five major groups of
natural products and are classified as alkaloids.2-9
Recently many cyclic peptides have been isolated from
marine microorganisms such as the Okinawan marine
sponge Theonella sp.4 The 2-bromotryptophans were
found to be constituents of a number of these cyclic
peptides,5-9 and representatives of this family are shown
in Figure 1. Konbamide (1) has been shown to antago-
nize the effects of calmodulin in calmodulin-activated
brain phosphodiesterase with an IC50 of 1 × 10-4 mol/
dm3.7 It is well-known that calmodulin,10 a Ca2+-binding
protein, regulates many cellular functions as a key
mediator of signal transduction in mammalian cells.
Furthermore, the related orbiculamide A (2a ) was found
to be cytotoxic against P388 murine leukemia cells (IC50
4.7 µg/mL).6 Keramamides B-D (3-5) have been shown
to be potent inhibitors of the generation of the superoxide
response of human neutrophiles elicited with fMLP,8
while keramamide E (6) exhibited cytotoxic activity
against L1210 murine leukemia cells (IC50 1.60 µg/mL)
and KB human epidermoid carcinoma cells (IC50 1.55 µg/
mL).9 Keramamide H (7) exhibited weak cytotoxicity
against the two types of cells mentioned in the preceding
sentence (IC50 ∼10 µg/mL).9 On the other hand, jaspa-
mide (8),5,11 a marine cyclodepsipeptide, has been found
to possess antifungal, antihelminthic, insecticidal, and
ichthyotoxic activity. All of these marine cyclic peptides
contain a 2-bromotryptophan unit (see 8) while most of
them contain a 2-bromo-5-hydroxytryptophan. In con-
trast, the unusual 5-hydroxy-6-chlorotryptophan was
found to be a constituent of keramamide A (9),12 and this
peptide exhibited inhibitory activity against sarcoplasmic
reticulum Ca2+-ATPase (IC50 3 × 10-4 mol/dm3). The
presence of the unusual tryptophan amino acids in these
cyclic peptides and their biological profiles4-6,9,11,13 ren-
dered these indoles attractive targets for synthesis
capable of extension for SAR studies. The optically active
substituted tryptophans or derivatives described below
are important units for the synthesis of these cyclic
peptides as well as serving as building blocks for the total
synthesis of indole alkaloids such as 19,20-dehydro-10-
methoxytalcarpine and sarpagine. The total syntheses
of a number of Alstonia alkaloids (from D-tryptophan)14-16
has been reported, consequently the enantiospecific
synthesis of ring-A alkoxylated tryptophans would pro-
vide useful building blocks to prepare the sarpagine
alkaloids.17,18
In 1995, Ashworth et al. reported the first total
synthesis of jaspamide (8).19 During the course of the
preparation of this paper, Schmidt and Weinbrenner
reported the syntheses of two isomers of konbamide (1).20
Previous syntheses20-24 of optically active 2-bromotryp-
tophans relied on the bromination of multiprotected
tryptophans using brominating agents such as NBS and
pyridinium bromide perbromide. These methods gener-
X Abstract published in Advance ACS Abstracts, October 1, 1997.
(1) This study was reported in preliminary form in the following:
(a) Zhang. P; Liu, R.; Cook, J . M. Tetrahedron Lett. 1995, 36, 3103. (b)
Zhang. P; Liu, R.; Cook, J . M. Tetrahedron Lett. 1995, 36, 7411. (c)
Zhang. P; Liu, R.; Cook, J . M. Tetrahedron Lett. 1995, 36, 9133.
(2) Pelletier, S. W. Chemistry of the Alkaloids; Van Nostrand
Reinhold Book Corporation: New York, 1970.
(3) Glasby, J . S. Encyclopedia of the Alkaloids; Plenum Press: New
York, 1975; Vols. I-III.
(4) Kobayashi, J .; Ishibashi, M. Chem. Rev. 1993, 93, 1753.
(5) Braekman, J . C.; Daloze, D.; Moussiaux, B. J . Nat. Prod. 1987,
50, 994.
(12) Kobayashi, J .; Sato, M.; Ishibashi, M.; Shigemori, H.; Naka-
mura, T.; Ohizumi, Y. J . Chem. Soc., Perkin Trans. 1 1991, 2609.
(13) Ishibashi, M.; Li, Y.; Sato, M.; Kobayashi, J . Nat. Prod. Lett.
1994, 4, 293.
(14) Zhang, L. H.; Cook, J . M. J . Am. Chem. Soc. 1990, 112, 4088.
(15) Fu, X.; Cook, J . M. J . Am. Chem. Soc. 1992, 114, 6910.
(16) Bi, Y.; Zhang, L. H.; Hamaker, L. K.; Cook, J . M. J . Am. Chem.
Soc. 1994, 116, 9027.
(17) Hamaker, L. K.; Cook, J . M. In Alkaloids: Chemical and
Biological Perspectives; Pelletier, S. W., Ed.; Elsevier Science: Am-
sterdam, 1995; Vol. 9, p 23.
(6) Fusetani, N.; Sugawara, T.; Matsunaga, S. J . Am. Chem. Soc.
1991, 113, 7811.
(7) Kobayashi, J .; Sato, M.; Murayama, T.; Ishibashi, M.; Wa¨lchi,
M. R.; Kanai, M.; Shoji, J .; Ohizumi, Y. J . Chem. Soc., Chem. Commun.
1991, 1050.
(18) Bi, Y.; Hamaker, L. K.; Cook, J . M. In Studies in Natural
Products Chemistry, Bioactive Natural Products, Part A; Basha, F. Z.,
Rahman, A., Eds.; Elsevier Science: Amsterdam, 1993; Vol. 13, p 383.
(19) Ashworth, P.; Broadbelt, B.; J ankowski, P.; Kocienski, P.; Pimm,
A.; Bell, R. Synthesis 1995, 199.
(8) Kobayashi, J .; Itagaki, F.; Shigemori, H.; Ishibashi, M.; Taka-
hashi, K.; Ogura, M.; Nagasawa, S.; Nakamura, T.; Hirota, H.; Ohta,
T.; Nozoe, S. J . Am. Chem. Soc. 1991, 113, 7812.
(9) Kobayashi, J .; Itagaki, F.; Shigemori, H.; Takao, T.; Shimonishi,
Y. Tetrahedron 1995, 51, 2525.
(10) Hidaka, H.; Yamaki, T.; Totsuka, T.; Asano, M. Mol. Pharmacol.
1978, 15, 55.
(20) Schmidt, U.; Weinbrenner, S. Synthesis 1996, 28.
(21) Grieco, P. A.; Hon, Y. S.; Perez-Medrano, A. J . Am. Chem. Soc.
1988, 110, 1630.
(22) Chu, K. S.; Negrete, G. R.; Konopelsky, J . P. J . Am. Chem. Soc.
1991, 56, 1993.
(23) Rao, R.; Gujar, M. K.; Nallagandu, B. R.; Bhandari, A. Tetra-
hedron Lett. 1993, 34, 7085.
(11) Inman, W.; Crews, P. J . Am. Chem. Soc. 1989, 111, 2822.
(24) Phillips, R. S.; Cohen, L. A. J . Am. Chem. Soc. 1988, 106, 2023.
S0022-3263(97)01067-0 CCC: $14.00 © 1997 American Chemical Society

7448 J . Org. Chem., Vol. 62, No. 21, 1997
Liu et al.
F igu r e 1.
ally suffer from the inability to provide the desired
hydroxy-substituted tryptophans in yields high enough
for further transformation or provide entry into only one
enantiomer. During research directed toward the total
synthesis of indole alkaloids,17,18 a regiospecific bromi-
nation procedure for 3-methylindoles was developed and
provided a route to various optically active substituted
tryptophans. This approach employed the Scho¨llkopf
chiral auxiliary, the synthesis of which can be scaled up
to the 500 g level and provides entry into either enanti-
omer.25,26 The regiospecific bromination of various sub-
stituted 3-methylindoles at either the C(3) alkyl moiety
or the C(2) position as well as the synthesis of 2-bromo-
tryptophans from bifunctional dibromoindoles 22a ,b
prepared via this regiospecific bromination process is
described below.
When N(1)-protected 5- or 6-methoxy-3-methylindoles
were stirred with NBS under free radical conditions
(benzoyl peroxide), electrophilic attack at the C(2) posi-
tion and free radical bromination of the 3-methyl group
were found to be competing processes which afforded the
3-(bromomethyl)indoles accompanied by some of the
2-bromo-3-methylindole regioisomer. The competition
between electrophilic and free radical bromination is well
recognized27,28 in methyl-substituted anisoles when they
are treated with NBS. To the best of our knowledge, the
related competing bromination of (Na-) protected 3-meth-
ylindoles has not been studied previously.
(25) Scho¨llkopf, U.; Lonsky, R.; Lehr, P. Liebigs Ann. Chem. 1985,
413.
(26) Zhang, P.; Cook, J . M. Synth. Commun. 1995, 25, 3883.
(27) Gruter, G. M.; Akkerman, O. S.; Bickelhaupt, F. J . Org. Chem.
1994, 59, 4473 and references cited therein.
(28) Goldberg, Y.; Bensimon, C.; Alper, H. J . Org. Chem. 1992, 57,
6374.

Bromination of 3-Methylindoles with NBS
J . Org. Chem., Vol. 62, No. 21, 1997 7449
zenesulfonyl)-5-bromo-3-(bromomethyl)indole.30 In ad-
dition, Cugnon de Sevricourt et al. reported the bromi-
nation of 3-methylbenzofuran at either the 2-position or
the 3-methyl position.31
Sch em e 1
However, when the parent (Na-H) 3-methylindoles such
as 12a and 12c were subjected to the above AIBN-
mediated radical bromination process, bromination at the
3-methyl group was not observed (Scheme 5). Instead,
electrophilic bromination took place at C(2) to provide
only 2-bromo-3-methylindoles 15h and 15i, respectively
(Table 3). These results illustrate that bromination of
3-methylindole at the 3-methyl group requires the deac-
tivation of the indole core by an electron-withdrawing
group (Na) to prevent bromination at C(2). In the absence
of deactivation at the N(1) position, the unprotected
3-methylindoles remain electron rich, promoting the
electrophilic bromination at the C(2) position and domi-
nating the bromination process to afford only attack at
C(2).
Although the presence of an electron-withdrawing
group at the N(1) position of 13a ,b retarded reaction at
the C(2) position, the electrophilic bromination of indoles
13a ,b occurred readily at C(2) when they were stirred
with NBS in the absence of a radical initiator (Scheme
3). In the case of 13a ,b, two contrasting factors were
involved in the electrophilic vs free radical process. Even
though indoles are reactive aromatic systems,32 the
presence of an electron-withdrawing group at the N(1)
position would be expected to deactivate them to elec-
trophilic attack. However, since the methoxyl group has
been employed to promote the electrophilic bromination
of methyl-substituted anisoles,27 presumably it plays the
same role in the bromination of indoles 13a ,b at the C(2)
position. Consequently, deactivation of the indole 2,3-
double bond by the N(1) protecting group and activation
by the methoxyl group at the C(6) position of indoles
13a ,b are delicately balanced. A slight change in reac-
tion conditions in the bromination process promotes the
reaction in the direction of either the electrophilic or free
radical bromination process. Moreover when indoles
13c-f, which are devoid of a 5-methoxyl group, were
treated with NBS in the absence of AIBN, only 3-(bro-
momethyl)indoles 14c-f were observed (Scheme 4). The
presence of the N(1) deactivating group and the absence
of a methoxyl group promotes bromination of the 3-meth-
ylindole carbon rather than attack at C(2). Presumably,
the radical bromination of 13c-f to provide 14c-f in the
absence of AIBN was initiated by heat or light.
Clearly, the results demonstrated that the regiospecific
bromination of 3-methyl-5-methoxyindoles can be con-
trolled by judicious choice of the reaction conditions and
the choice of the protecting group at the N(1) position.
In the presence of an activating group on ring-A such as
a methoxyl moiety, the protection of indoles at the N(1)
position should be accomplished before the bromination
is carried out. The 3-methylindoles protected in this
fashion (e.g., 13a ,b) should lead to either 3-(bromometh-
yl)indoles or 2-bromo-3-methylindoles on the basis of the
choice of the reaction conditions (free radical vs electro-
philic). In the absence of ring-A oxygenated activating
groups, free radical bromination at the 3-methyl group
should be facilitated by the electron-withdrawing group
The efficient synthesis of 3-methylindoles on multi-
hundred-gram scale is illustrated in Schemes 1 and 2.
Ethyl 3-methylindole-2-carboxylates 11a and 11b were
prepared from the proper aniline 10 and ethyl R-ethyl-
acetoacetate by the Fischer indole cyclization via a J app-
Klingmann azo-ester intermediate. This process has
been fully explored by Abramovitch and Shapiro as well
as reviewed.29 Alkaline hydrolysis of the ester functions
and subsequent copper/quinoline-mediated decarboxyla-
tion of the corresponding carboxylic acids which resulted
afforded the 3-methylindoles 12a and 12b, respectively,
in excellent yield. The protection of the 3-methylindoles
with either di-tert-butyl dicarbonate or benzenesulfonyl
chloride furnished the protected 3-methylindoles repre-
sented by 13a -d .
With the N(1)-protected 3-methylindoles 13a ,b in
hand, the bromination of 3-methylindoles with NBS was
carried out under two sets of conditions (Scheme 3). In
the electrophilic bromination process, 3-methylindoles
13a ,b were simply heated with NBS in refluxing carbon
tetrachloride in the absence of the radical initiator AIBN
to provide 14a ,b, respectively. In the radical bromination
process, the 3-methylindoles were heated in refluxing
CCl4 and then treated with NBS and AIBN to afford
15a ,b, respectively (see Table 1). The AIBN was added
in portions to the refluxing carbon tetrachloride solution
over time.
On the other hand, as shown in Scheme 4, treatment
of 13c-f with NBS in the presence or absence of the
radical initiator (AIBN) at reflux in CCl4 afforded only
the corresponding regioisomeric 3-(bromomethyl)indoles
14c-f and in excellent yield (Table 2). The free radical
reaction at the 3-methyl moiety of indoles 13c-f was not
surprising since the N(1) protecting group deactivated
the indole core and permitted the radical bromination
process as the principal pathway. A similar bromination
has been previously observed in the formation of 1-(ben-
(30) Nagarathnam, D.; J ohnson, M. E. Synth. Commun. 1993, 23,
2011.
(31) Sevricourt, M. C. d.; Robba, M. Bull. Soc. Chim. Fr. 1977, 139.
(32) Gilchrist, T. L. Heterocyclic Chemistry; J ohn Wiley & Sons
Inc.: New York, 1985; p 161.
(29) Abramovitch, R. A.; Shapiro, D. S. J . Chem. Soc. 1956, 4589.

7450 J . Org. Chem., Vol. 62, No. 21, 1997
Liu et al.
Sch em e 2
Sch em e 3
Sch em e 4
Ta ble 1. Br om in a tion of Dea ctiva ted 5-Meth oxyin d oles
by NBS
Ta ble 2. Br om in a tion of Dea ctiva ted In d oles by NBS
reaction
conditions
(initiator, time)
melting
point
(°C)
product
(yield, %)
reaction
melting
point
compd
R
conditions
product
compd
R
R′
(initiator, time) (yield, %)
(°C)
13a
13a
13b
13b
SO2C6H5
SO2C6H5
BOC
AIBN, 2 h
none, 3 h
AIBN, 1 h
none, 2 h
14a (83)
15a (86)
14b (92)
15b (95)
116-118
148-150
a
13c
13c
13d
13d
13e
13e
13f
13f
SO2C6H5 5-Cl
SO2C6H5 5-Cl
BOC
AIBN, 2 h
none, 10 h
AIBN, 2 h
none, 9 h
14c (93) 139-142
14c (90) 139-142
14d (91) 100-102
14d (89) 100-102
14e (94) 132-134
14e (92) 132-134
BOC
82-84
5-Cl
5-Cl
H
H
H
BOC
a
14b was converted into 3-(hydroxymethyl)indole (mp 144-
SO2C6H5
SO2C6H5
BOC
AIBN, 3 h
none, 10 h
AIBN, 2 h
none, 10 h
146 °C) and was thus characterized.
14f (95)
14f (92)
106-107
106-107
at the N(1) position of the 3-methylindole. On the other
hand, in order to brominate 3-methylindoles at the C(2)
position even when they lack the ring-A activating
substituent, the bromination should proceed before the
(Na-) protection sequence is executed.
The 5-methoxytryptophan (20) and 5-hydroxy-6-chlo-
rotryptophan (21c) were chosen as initial synthetic
targets for the regiospecific bromination/Scho¨llkopf pro-
tocol (Schemes 6 and 7). When 3-(bromomethyl)indoles
14a (Scheme 6) and 14g (Scheme 7) were treated
(individually) with the anion of the Scho¨llkopf chiral
auxiliary, only the desired trans diastereomers 16 and
17, respectively, were obtained. The acidic hydrolysis of
the chiral auxiliary furnished the protected tryptophan
BOC
H
ethyl esters 18 (Scheme 6) and 19 (Scheme 7), respec-
tively. The careful hydrolysis of tryptophan ester 19 with
varying amounts of boron tribromide afforded the various
optically active 6-chloro-5-hydroxytryptophan derivatives
21a -c regiospecifically, which can be used for the total
synthesis of keramamide A (9). The optical purity of
esters 21a and 21b was determined using Eu(hfbc)3, an
optically active NMR chiral shift reagent which imparts
a different chemical shift pattern to each enantiomer; an
approximate 3:1 molar ratio of ligand to shift reagent was
optimal. This method was validated with racemic mate-
rial as well as spiked (()-material. In an NMR doping

Bromination of 3-Methylindoles with NBS
J . Org. Chem., Vol. 62, No. 21, 1997 7451
Sch em e 5
Sch em e 8
tophan (20). The optical rotation of compound 20 was
virtually identical to the literature value.33 Both the (+)-
and (-)-enantiomers of these amino acids were prepared
in optically pure form by varying the Scho¨llkopf chiral
auxiliary.25,26 The D-series can be prepared from L-valine
while the L-series originates from D-valine. In addition,
the Scho¨llkopf auxiliary can be prepared on 400-500 g
scale with ease in either enantiomeric form.34
Ta ble 3. Br om in a tion of In d oles by NBS
reaction
melting
point
(°C)
conditions
product
compd
R′
(initiator, time)
(yield, %)
12a
12a
12c
12c
5-Cl
5-Cl
H
AIBN, 1 h
none, 1 h
AIBN, 1 h
none, 3 h
15h (87)
15h (98)
15i (92)
15i (97)
96-98
96-98
91-93
91-93
H
The 2-bromo-3-(bromomethyl)indoles appeared to be
reasonable starting materials for the synthesis of the
unusual 2-bromotryptophans present in the marine
natural products illustrated in Figure 1. The bromina-
tion of the BOC-protected 5-methoxy-3-methylindole 13b
was initially carried out with 2 equiv of NBS to facilitate
bromination at the 2-position via electrophilic substitu-
tion. This was to be followed by reaction at the 3-methyl
position via the free radical process by the addition of
AIBN at a latter stage. Unfortunately, with 13b it was
found that bromination took place rapidly at the 2-posi-
tion but was followed by bromination at the 4- and
6-positions. Two tribromoindoles, 1-BOC-2,4-dibromo-
3-(bromomethyl)-5-methoxyindole and 1-BOC-2,6-dibromo-
3-(bromomethyl)-5-methoxyindole were isolated and then
Sch em e 6
1
identified by H NMR and mass spectroscopy. Further
Sch em e 7
experiments established that the desired dibromoindole
22a was best prepared by heating the mixture of indole
13b with 1 equiv of NBS followed by addition of another
equivalent of NBS as an admixture with AIBN (Scheme
8). In this manner the regiocontrolled dibromination was
achieved in good yield. On the other hand, for jaspamide
(8), bromination of the unsubstituted 3-methylindole 12c
at the 2-position was required before BOC protection at
the (Na-) position, as noted previously. Consequently, the
indole 12c was converted into indole 23 by electrophilic
bromination at the 2-position with NBS, followed by
protection with the BOC group at the (Na-) position. The
free radical bromination of BOC-protected indole 23 at
the 3-methyl moiety then furnished the desired dibro-
moindole 22b, as shown in Scheme 8.
With the key dibromoindoles 22a ,b in hand, the
synthesis of the 2-bromotryptophans 26a -c was readily
executed, as illustrated in Scheme 9. Briefly, dibromoin-
dole 22a or 22b was treated with the anion of the
Scho¨llkopf chiral auxiliary to provide a mixture of dia-
stereomers 24a :24b or 24c:24d in a ratio of approxi-
mately 92:8, respectively. Interestingly, the alkylation
of the Scho¨llkopf chiral auxiliary with a 3-(bromometh-
experiment addition of 2% of the enantiomer to 21a or
21b resulted now in observation of this minor isomer;
consequently 21a and 21b were determined to be at least
98% ee. The removal of the benzenesulfonyl group from
18 (Scheme 6) was readily carried out under basic
conditions to furnish the optically pure 5-methoxytryp-
(33) Porter, J .; Dykert, J .; Rivier, J . Int. J . Peptide Protein Res. 1987,
30, 13.
(34) Liu, R. Ph.D. Thesis, University of WisconsinsMilwaukee,
1996.

7452 J . Org. Chem., Vol. 62, No. 21, 1997
Liu et al.
resolution mass spectral data (EI/CI) were obtained on a
Hewlett-Packard 5985 B GC-mass spectrometer. High-
resolution mass spectral data were taken on a VG auto
spectrometer (double-focusing high-resolution GC/mass spec-
trometer, U.K.). Optical rotations were measured on a J ASCO
DIP-370 polarimeter. Microanalyses were performed on a
Perkin-Elmer 240C carbon, hydrogen, and nitrogen analyzer.
Analytical TLC plates employed were E. Merck Brinkman UV
active silica gel (kieselgel 60 F254) on plastic while silica gel
60b for flash chromatography was purchased from E. M.
Laboratories. All chemicals were purchased from Aldrich
Chemical Co. unless otherwise indicated. Experiments with
the Scho¨llkopf chiral auxillary on large scale have been
reported elsewhere.34
Sch em e 9
Eth yl 5-Ch lor o-3-m eth ylin d ole-2-ca r boxyla te (11b).25,29
To a mixture of 4-chloroaniline (50 g, 0.32 mol), concd aqueous
HCl (80 mL), and water (140 mL) was added dropwise a
solution of NaNO2 (24.7 g, 0.35 mol) in 30 mL of water at -5
°C. After addition, the mixture was stirred at 0 °C for 15 min
and brought to pH 3-4 by addition of sodium acetate (21 g,
0.27 mol). In a separate flask, a solution of ethyl R-ethylaceto-
acetate (57.4 g, 0.35 mol) in ethanol (250 mL) at 0 °C was
treated with an aqueous solution of KOH (0.35 mol in 30 mL
of H2O), followed by addition of ice (400 g). The diazonium
salt prepared above was immediately added to this alkaline
solution. The mixture was then adjusted to pH 5-6 and
stirred at 0 °C for 3 h. After the solution was kept for a further
12 h at 4 °C, the mixture was extracted with ethyl acetate (4
× 100 mL). The combined extracts were washed with brine
and dried (MgSO4). Most of the solvent was removed under
reduced pressure, and the liquid residue was added dropwise
to a solution of 14.5% ethanolic HCl at 78 °C (or polyphosphoric
acid at 120 °C). This reaction is exothermic, and the oil is
added carefully to the solution of ethanolic hydrogen chloride.
After addition, the mixture was held at 78 °C for 2 h. The
solvent was removed under reduced pressure, and the residue
was treated with water (100 mL) and CH2Cl2 (300 mL). The
aqueous layer was extracted with CH2Cl2 (3 × 100 mL), and
the combined organic layers were washed with brine and dried
(Na2SO4). Purification of the residue on a short wash column
(silica gel, ethyl acetate/hexane, 1:3) gave the ester 11b as a
white solid (63 g, 74%): mp 162-163 °C; IR (KBr) 3337, 1669,
yl)indole in the indole-2(H) series proceeded in enan-
tiospecific fashion. No minor diastereomer was detected
in contrast to the results with 22a ,b observed here. The
desired trans diastereomer 24a or 24b was easily sepa-
rated from 24c or 24d by flash chromatography (silica
gel) and hydrolyzed under acidic conditions to furnish the
L(+)-1-BOC-2-bromo-5-methoxytryptophan ethyl esters
25a or 25b, respectively, in high yield (Scheme 9). The
D-valine ethyl ester which results from hydrolysis of the
chiral auxiliary was readily recovered by Kugelrohr
distillation. It was employed later to prepare more of
the Scho¨llkopf chiral auxiliary. The BOC-protected tryp-
tophan ethyl esters 25a or 25b were (individually) readily
converted into the 2-bromotryptophans 26a , 26b, or 26c
when treated with varying amounts of boron tribromide
as shown in Scheme 9 (see Experimental Section for
details).
In summary, the regiospecific bromination of 3-meth-
ylindoles at either the C(2) position or the C(3) alkyl
moiety has been developed. This process was employed
for the enantiospecific syntheses of (+)- or (-)-5-meth-
oxytryptophan 20 and 5-hydroxy-6-chlorotryptophan 21c
as well as for the facile synthesis of the optically active
2-bromotryptophans from the dibromoindole building
blocks. These unusual tryptophan amino acids or amino
esters can be used for the synthesis of the biologically
active marine cyclic peptides represented in Figure 1. In
addition, the bromoindoles should be useful in vinylation,
acetylation, and arylation reactions via transition metal
catalysts and provide versatile building blocks for the
synthesis of ring-A alkoxylated indole alkaloids.17,18
1452 cm-1 1H NMR (250 MHz, CDCl3) δ 1.42 (t, 3H, J ) 7
;
Hz), 2.55 (s, 3H), 4.40 (q, 2H, J ) 7 Hz), 7.23 (m, 2H), 7.61 (s,
1H), 8.67 (s, 1H); MS (EI) m/ e (relative intensity) 239 (M+,
39), 237 (M+, 80), 191 (100), 163 (35), 128 (37), 101 (20). Anal.
Calcd for C12H12NO2Cl: C, 60.64; H, 5.09; N 5.89. Found: C,
60.77; H, 5.34; N, 5.67.
Eth yl 6-Ch lor o-5-m eth oxy-3-m eth ylin d ole-2-ca r boxy-
la te (11g). The indole 11g was prepared in 72% yield from
3-chloro-p-anisidine (10g) following the procedure described
above for the preparation of 11b. The regioisomer ethyl
4-chloro-5-methoxy-3-methylindole-2-carboxylate (11h ) was
obtained as a minor product. The ratio of 11g and 11h was
1
determined to be 14:1 by intergration of the H NMR spectrum
of the mixture. 11g: mp 187.7-188.5 °C; IR (KBr) 3330, 2935,
1
1662, 1538 cm-1; H NMR (250 MHz, CDCl3) δ 1.41 (t, 3H, J
) 7.1 Hz), 2.55 (s, 3H), 3.94 (s, 3H), 4.40 (q, 2H, J ) 7.1 Hz),
7.04 (s, 1H), 7.38 (s, 1H), 8.62 (s, 1H); MS (EI) m/ e (relative
intensity) 269 (M+, 34), 267 (M+, 65), 221 (100), 206 (35), 178
(20), 150 (20). Anal. Calcd for C13H14NO3Cl: C, 58.32; H, 5.27;
N 5.23. Found: C, 58.28; H, 5.30; N, 5.12. 11h : 1H NMR
(250 MHz, CDCl3) δ 1.41 (t, 3H, J ) 7.1 Hz), 2.87 (s, 3H), 3.91
(s, 3H), 4.40 (q, 2H, J ) 7.1 Hz), 7.05 (d, 1H, J ) 8.0 Hz), 7.19
(d, 1H, J ) 8.0 Hz); MS (EI) m/ e (relative intensity) 269 (M+,
34), 267 (M+, 65).
5-Ch lor o-3-m eth ylin dole (12b). A mixture of ethyl 5-chlo-
ro-3-methylindole-2-carboxylate 11b (59.2 g, 0.25 mol), EtOH
(150 mL), KOH pellets (85%, 49 g, 0.75 mol), and water (100
mL) was heated to reflux for 1 h. The volume was reduced to
30 mL under reduced pressure and brought to acidic pH with
an aqueous solution of 3 N HCl. The precipitate which
resulted was collected on a filter, washed with distilled water,
and dried in a vacuum oven at 80 °C to afford 5-chloro-3-
methylindole-2-carboxylic acid as a white solid (51 g, 99%).
This acid (21 g, 0.1 mol) was then heated to reflux in a well-
Exp er im en ta l Section
Melting points were taken on a Thomas-Hoover melting
point apparatus or an Electrothermal Model IA8100 digital
melting point apparatus and are reported uncorrected. The
1H NMR spectra were recorded on a Bruker 250-MHz multiple-
probe instrument or a GE 500-MHz spectrometer. Infrared
spectra were recorded on
a Nicolet Dx FTIR DX V5.07
spectrometer or a Mattson Polaris IR-10400 instrument. Low-

Bromination of 3-Methylindoles with NBS
J . Org. Chem., Vol. 62, No. 21, 1997 7453
stirred mixture of distilled quinoline (50 mL) and copper
powder (0.8 g) under nitrogen for 2.5 h. The copper powder
was removed by filtration, after which the filtrate was brought
to pH 2-3 at 0 °C with an aqueous solution of 6 N HCl. The
solution which resulted was extracted with diethyl ether (4 ×
100 mL). The combined organic layers were washed with brine
and dried (MgSO4). The solvent was removed under reduced
pressure to afford 5-chloro-3-methylindole 12b as a brown solid
(15.1 g, 94%): mp 112-114 °C (lit.35 mp 114-116 °C); IR (KBr)
9H), 2.23 (s, 3H), 7.25 (dd, 1H, J ) 2 and 9 Hz), 7.35 (s, 1H),
7.45 (d, 1H, J ) 2 Hz), 8.04 (d, 1H, J ) 9 Hz); MS (EI) m/ e
(relative intensity) 267 (M+, 8), 265 (M+, 24), 209 (54), 164
(100), 128 (34), 101 (50); HRMS for C14H16NO2Cl calcd
265.0869, found 265.0868. Anal. Calcd for C14H16NO2Cl: C,
63.39; H, 6.06; N, 5.28. Found: C, 63.33; H, 6.20; N, 5.08.
1-(ter t-Bu tyloxyca r bon yl)-3-m eth ylin dole (13f) was pre-
pared in 93% yield following the procedure for the preparation
of 13b. 13f: mp 106-107 °C; IR (KBr) 2990, 1715, 1386 cm-1
;
1
2978, 1457 cm-1; H NMR (250 MHz, CDCl3) δ 2.21 (s, 3H),
1H NMR (250 MHz, CDCl3) δ 1.67 (s, 9H), 2.28 (s, 3H), 7.25-
7.38 (m, 3H), 7.51 (dd, J ) 6.8, 1.7 Hz, 1H), 8.12 (d, J ) 7.7
Hz, 1H); MS (EI) m/ e (relative intensity) 231 (M+, 30), 175
(75), 131 (72), 130 (100), 103 (10). This material was used
directly in a later step (see below).
7.11 (d, 1H, J )2 Hz), 7.15 (d, 1H, J ) 2 Hz), 7.20 (s, 1H),
7.45 (s, 1H), 8.05 (s, 1H); MS (EI) m/ e (relative intensity) 167
(M+, 57), 165 (M+, 92), 154 (53), 129 (40), 102 (28), 65 (30);
HRMS for C9H8NCl calcd 165.0345; found: 165.0357.
6-Ch lor o-5-m eth oxy-3-m eth ylin d ole (12g) was prepared
in 95% yield following the procedure described for the prepara-
tion of 12b. 12g: IR (KBr) 2935, 867, 717 cm-1; 1H NMR (250
MHz, CDCl3) δ 2.25 (s, 3H), 3.95 (s, 3H), 6.94 (s, 1H), 7.01 (s,
1H), 7.36 (s, 1H), 7.75 (s, 1H); MS (EI) m/ e (relative intensity)
197 (M+, 32), 195 (M+, 94), 182 (33), 180 (100), 152 (89), 117
(23), 89 (33). Anal. Calcd for C10H10NOCl: C, 61.39; H, 5.15;
N, 7.16. Found: C, 61.54; H, 5.04; N, 6.98.
1-(ter t-Bu tyloxyca r bon yl)-6-ch lor o-5-m eth oxy-3-m eth -
ylin d ole (13g) was prepared in 95% yield using the same
procedure as that described above for the preparation of 13b.
13g: mp 126.8-132.1 °C; IR (KBr) 3426, 2973, 1729, 1475
1
cm-1; H NMR (250 MHz, CDCl3) δ 1.63 (s, 9H), 2.22 (s, 3H),
3.94 (s, 3H), 6.92 (s, 1H), 7.30 (s, 1H), 8.15 (s, 1H); MS (EI)
m/ e (relative intensity) 297 (M+, 25), 295 (M+, 71), 239 (93),
195 (100), 180 (92), 152 (24); HRMS for C15H18NO3Cl calcd
295.0975, found 295.0969. Anal. Calcd for C15H18NO3Cl: C,
61.02; H, 6.15; N 4.75. Found: C, 61.15; H, 6.13; N, 4.63.
1-(Ben zen esu lfon yl)-3-(b r om om et h yl)-5-m et h oxyin -
d ole (14a ). A solution of 13a 26 (35.5 g, 0.118 mol) in CCl4
(500 mL) was heated to reflux after which N-bromosuccinimide
(22.2 g, 0.123 mol) and AIBN (500 mg) were carefully added
in a portionwise manner over 5 min. After completion of the
addition, three portions of AIBN (3 × 200 mg) were added,
one each 30 min. After 3 h the mixture was cooled to rt and
the succinimide which resulted was filtered off and washed
with CCl4 (3 × 50 mL). The solvent was removed under
reduced pressure to yield a brown solid. A further purification
by recrystallization from diethyl ether afforded 14a as off-
white colored crystals (37 g, 82.5%): mp 116-118 °C; IR (KBr)
1-(Ben zen esu lfon yl)-3-m eth ylin d ole (13e). To a solution
of skatole (12c) (1.31 g, 10 mmol) in THF (50 mL) was added
n-BuLi (2.5 M, 4.4 mL, 11 mmol in hexane) at -78 °C under
nitrogen. The white suspension which resulted was kept at
-78 °C for 15 min and slowly warmed to rt. After 2 h at rt,
the mixture was cooled to -78 °C and treated with benzene-
sulfonyl chloride (1.40 mL, 11 mmol). After 20 min at -78
°C, the reaction solution was slowly warmed to rt, stirred
overnight, and treated with a saturated aqueous solution of
NH4Cl (5 mL). The solvent was removed under reduced
pressure, and the residue was taken up in CH2Cl2 (30 mL).
The organic layer was separated, washed with brine (20 mL),
and dried (Na2SO4). After removal of solvent under reduced
pressure, the residue was purified by flash chromatography
(silica gel, hexane/ethyl acetate, 8/1) to afford 13e as an off-
white solid (2.54 g, 94%): mp 126-127 °C. 1H NMR (250 MHz,
CDCl3) δ 2.24 (s, 3H), 7.2-7.55 (m, 7H), 7.86 (dd, 2H, J ) 9.0
and 1.6 Hz), 8.01 (d, 1H, J ) 8.0 Hz); MS (EI) m/ e (relative
1
3103, 2856, 1607 cm-1; H NMR (250 MHz, CDCl3) δ 3.85 (s,
3H), 4.60 (s, 2H), 6.95 (dd, 1H, J ) 8.7, 2.4 Hz), 7.05 (d, 1H, J
) 2.3 Hz), 7.45 (t, 2H, J ) 7.6 Hz), 7.55 (d, 1H, J ) 8.0 Hz),
7.65 (s, 1H), 7.85 (m, 3H); MS (EI) m/ e (relative intensity)
381 (M+, 21.4), 379 (M+, 18.3), 240 (51.1), 238 (53.4), 160 (39.1),
159 (100), 116 (77). Anal. Calcd for C16H14BrNSO3: C, 50.54;
H, 3.71; N, 3.68. Found: C, 50.36; H, 3.47; N, 4.01.
intensity) 271 (M+, 14.3), 130 (100.0). Anal. Calcd for C15H13
-
NO2S: C, 66.42; H, 4.80; N 5.17. Found: C, 66.77; H, 4.87;
N, 5.10.
1-(Ben zen esu lfon yl)-5-ch lor o-3-m eth ylin d ole (13c) was
prepared in 90% yield following the procedure for the prepara-
tion of 13e. 13c: mp 140.9-142.2 °C; IR (KBr) 3448, 3111,
1-(ter t-Bu t yloxyca r b on yl)-3-(b r om om et h yl)-5-m et h -
oxyin d ole (14b) was prepared in 87% yield following the
procedure for the preparation of 14a . 14b: a brown oil; H
NMR (250 MHz, CDCl3) δ 1.66 (s, 9H), 3.89 (s, 3H), 4.66 (s,
2H), 6.97 (dd, 1H, J ) 9.1, 2.6 Hz), 7.12 (d, 1H, J ) 2.5 Hz),
7.13 (s, 1H), 8.04 (d, 1H, J ) 8.9 Hz). MS (EI) m/ e (relative
intensity) 341 (M+, 19), 339 (M+, 21), 285 (27), 283 (29), 241
(92), 239 (100), 226 (38), 224 (43), 159 (33), 116 (71).
1
1
2920, 1446 cm-1; H NMR (250 MHz, CDCl3) δ 2.20 (s, 3H),
7.30 (m, 2H), 7.32 (s, 1H), 7.40-7.55 (m, 3H), 7.80-7.90 (m,
3H); MS (EI) m/ e (relative intensity) 307 (M+, 11), 305 (M+,
33), 166 (31), 164 (100), 128 (43), 102 (45). Anal. Calcd for
C15H12NSO2Cl: C, 59.00; H, 3.90; N, 4.60. Found: C, 58.88;
H, 3.89; N, 4.49.
1-(Ben zen esu lfon yl)-3-(br om om eth yl)-5-ch lor oin d ole
(14c) was prepared in 93% yield following the procedure for
the preparation of 14a . 14c: mp 139-142 °C; IR (KBr) 3449,
1-(ter t-Bu t yloxyca r b on yl)-5-m et h oxy-3-m et h ylin d ole
(13b). A solution of 5-methoxy-3-methylindole26 (12.8 g, 79
mmol) in CH3CN (100 mL) under nitrogen was treated at rt
with di-tert-butyl dicarbonate (18.6 g, 83 mmol) and DMAP
(0.5 g, 4 mmol). The mixture was stirred at rt for 12 h and
the solvent removed under reduced pressure. The residue was
dissolved in ethyl acetate (100 mL), washed with an aqueous
solution of 1 N HCl (2 × 30 mL) and brine (50 mL), and dried
(Na2SO4). After removal of solvent under reduced pressure,
the residue solidified to afford 13b as a white solid in 95%
yield: mp 58-60 °C; IR (KBr) 2974, 1721, 1452 cm-1; 1H NMR
(250 MHz, CDCl3) δ 1.67 (s, 9H), 2.23 (s, 3H), 3.87 (s, 3H),
6.92 (dd, 1H, J ) 8.5, 2.6 Hz), 7.25 (s, 1H), 7.33 (br, 1H), 7.98
(d, 1H, J ) 8.4 Hz); MS (EI) m/ e (relative intensity) 261 (M+,
21.2), 205 (100.0), 161 (63.6), 146 (63.3). Anal. Calcd for
C15H19NO3‚1/4H2O: C, 67.92; H, 7.35; N 5.28. Found: C, 68.12;
H, 7.17; N, 5.26.
1
3141, 1579 cm-1; H NMR (250 MHz, CDCl3) δ 4.51 (s, 2H),
7.31 (s, 1H), 7.47 (m, 2H), 7.62 (s, 1H), 7.86 (m, 4H); MS (EI)
m/ e (relative intensity) 386 (M+, 3), 384 (M+, 10), 304 (36),
163 (50), 141 (100), 128 (26), 101 (2); HRMS for C15H11NO2-
SClBr calcd 384.6748, found 384.6756.
1-(ter t-Bu t yloxyca r b on yl)-3-(br om om et h yl)-5-ch lor o-
in d ole (14d ) was prepared in 91% yield via the method
described for the preparation of 14a . 14d : mp 100-102 °C;
1
IR (KBr) 3017, 1510 cm-1; H NMR (250 MHz, CDCl3) δ 1.60
(s, 9H), 4.6 (s, 2H), 7.35 (dd, 1H, J )2 and 8.7 Hz), 7.65 (d,
1H, J ) 2 Hz), 7.70 (s, 1H), 8.11 (d, 1H, J ) 8.7 Hz); MS (EI)
m/ e (relative intensity) 345 (M+, 5), 344 (2), 343 (4), 164 (100),
163 (45), 101 (40). The material was employed directly in a
later step.
1-(Ben zen esu lfon yl)-3-(br om om eth yl)in d ole (14e) was
prepared in 94% yield following the procedure for the prepara-
tion of 14a . 14e: mp 132-134 °C; IR (KBr) 3100, 2850, 1610
1-(ter t-Bu tyloxycar bon yl)-5-ch lor o-3-m eth ylin dole (13d)
was prepared in 95% yield following the procedure for the
preparation of 13b. 13d : a white solid; mp 91-92 °C; IR (KBr)
1
cm-1; H NMR (DMSO-d6) δ 4.89 (s, 2H), 7.30-7.45 (m, 2H),
1
3436, 2976, 1728 cm-1; H NMR (250 MHz, CDCl3) δ 1.67 (s,
7.55-7.72 (m, 4H), 7.90-8.05 (m, 4H). MS (EI) m/ e (relative
intensity) 350 (M+, 16.6), 348 (M+, 17.2), 270 (73.0), 141 (97.6),
129 (100.0). Anal. Calcd for C15H12BrNO2S‚1/2H2O: C, 50.15;
H, 3.62; N, 3.90. Found: C, 50.34; H, 3.40; N, 3.83.
(35) Fleming, I.; Woolias, M. J . Chem. Soc., Perkin Trans. 1 1979,
829.

7454 J . Org. Chem., Vol. 62, No. 21, 1997
Liu et al.
1-(ter t-Bu tyloxyca r bon yl)-3-(br om om eth yl)in d ole (14f)
was prepared in 95% yield following the procedure for the
preparation of 14a . 14f: mp 106-107 °C; 1H NMR (250 MHz,
CDCl3) δ 1.68 (s, 9H), 4.69 (s, 2H), 7.81-7.95 (m, 2H), 7.70
(m, 2H), 8.18 (d, J ) 7.8 Hz); MS (EI) m/ e (relative intensity)
311 (M+, 2.6), 309 (M+, 3.1), 174 (32.0), 130 (100). Anal. Calcd
for C14H16BrNO2: C, 54.19; H, 5.16; N 4.52. Found: C, 54.15;
H, 5.30; N, 4.73.
1-(ter t-Bu t yloxyca r b on yl)-3-(br om om et h yl)-6-ch lor o-
5-m eth oxyin d ole (14g) was prepared in 87% yield following
the procedure for the preparation of 14a . 14g: 1H NMR (250
MHz, CDCl3) δ 1.64 (s, 9H), 3.97 (s, 3H), 4.63 (s, 2H), 7.10 (s,
1H), 7.61 (s, 1H), 8.18 (s, 1H); IR (KBr) 2979, 1732, 1469, 1268,
1158, 744 cm-1. This indole 14g was employed directly in a
later step without further purification.
to afford 17 as an oil (14 g, 96%): IR (KBr) 2974, 1729, 1691
1
cm-1; H NMR (250 MHz, CDCl3) δ 0.69 (d, 3H, J ) 6.9 Hz),
0.94 (d, 3H, J ) 6.9 Hz), 1.21 (t, 3H, J ) 7.1 Hz), 1.32 (t, 3H,
J ) 7.1 Hz), 1.63 (s, 9H), 2.20 (m, 1H), 3.12 (d, 2H, J ) 4.8
Hz), 3.58 (t, 1H, J ) 3.4 Hz), 3.92 (s, 3H), 4.00-4.28 (m, 4H),
4.30 (q, 1H, J ) 4.6 Hz), 7.08 (s, 1H), 7.32 (s, 1H), 8.13 (s,
1H); 13C NMR (62.90 MHz, CDCl3) δ 14.1, 14.3, 16.7, 19.3, 28.2,
29.3, 31.8, 56.1, 56.6, 60.5, 60.6, 60.8, 83.4, 102.5, 116.7, 117.3,
120.1, 125.0, 129.6, 130.8, 149.3, 151.2, 162.2, 163.7; MS (EI)
m/ e (relative intensity) 565 (M+, 3), 237 (18), 212 (45), 194
(61), 169 (100), 141 (22), 113 (10). This material was employed
directly in a later step without further purification.
(S)-1-(ter t-Bu tyloxyca r bon yl)-6-ch lor o-5-m eth oxytr yp -
top h a n Eth yl Ester (19). To a solution of pyrazine 17 (5.05
g, 10 mmol) in THF (25 mL) at 0 °C was added an aqueous
solution of 2 N HCl (25 mL). The mixture was allowed to
warm to rt, stirred for 40 min, and poured into a cold aqueous
solution of NH4OH (final pH ∼9). The solution which resulted
was concentrated, and CH2Cl2 (20 mL) was added. The
aqueous layer was extracted with CH2Cl2 (2 × 30 mL). The
combined organic layers were washed with brine and dried
(Na2SO4). After removal of solvent under reduced pressure,
the valine ethyl ester which resulted from the hydrolysis of
the chiral auxiliary was removed by Kugelrohr distillation.
This valine ethyl ester could be reused. The residue obtained
was purified by flash chromatography (silica gel, ethyl acetate/
hexane, 1/4, followed by ethyl acetate) to afford 19 (3.68 g, 93%)
1-(ter t-Bu tyloxyca r bon yl)-2-br om o-5-m eth oxy-3-m eth -
ylin d ole (15b). A mixture of 3-methylindole 13b (1.31 g, 5
mmol) and NBS (0.98 g, 5.5 mmol) in anhydrous CCl4 (10 mL)
was heated to reflux under nitrogen. When all the NBS was
converted into succinimide, which floated on the surface of the
CCl4, the reaction solution was cooled to rt. The succinimide
was removed by filtration and washed with CCl4 (2 × 2 mL).
The combined filtrates were concentrated under reduced
pressure to afford 15b as a brown solid (1.61 g, 95%). The
residue was crystallized from a mixture of CCl4 and hexane
to afford 1-(tert-butyloxycarbonyl)-2-bromo-5-methoxy-3-meth-
1
ylindole (15b) as a white solid: mp 82-84 °C; H NMR (250
as a yellow solid: mp 118-120 °C; [R]30 ) +6.5 (c ) 1.9, in
MHz, DMSO-d6) δ 1.62 (s, 9H), 2.18 (s, 3H), 3.79 (s, 3H), 6.91
(dd, 1H, J ) 9.0, 2.5 Hz), 7.07 (d, 1H, J ) 2.4 Hz), 7.38 (d, 1H,
J ) 9.1 Hz). MS (EI) m/ e (relative intensity) 341 (M+, 18.9),
339 (M+, 21.0), 285 (27.4), 283 (28.6), 241 (92.1), 239 (100.0),
226 (38.3), 224 (43.4). Anal. Calcd for C15H18BrNO3: C, 52.94;
H, 5.29; N, 4.12. Found: C, 52.72; H, 5.41; N, 3.87.
D
CH2Cl2); IR (KBr) 3361, 2978, 1732 cm-1; 1H NMR (250 MHz,
CDCl3) δ 1.21 (t, 3H, J ) 7.2 Hz), 1.65 (s, 9H), 3.18 (m, 2H),
3.91 (m, 1H), 3.98 (s, 3H), 4.18 (q, 2H, J ) 7.1 Hz), 7.13 (s,
1H), 7.50 (s, 1H), 8.20 (br, 1H); MS (EI) m/ e (relative intensity)
398 (M+, 1.5), 396 (M+, 3.9), 237 (16.2), 194 (100), 179 (14),
163 (22), 102 (30); HRMS for C19H25N2O5Cl calcd 396.1452,
found 396.1441. Anal. Calcd for C19H25N2O5Cl: C, 57.55; H,
6.36; N 7.07. Found: C, 57.64; H, 6.23; N, 6.96.
1-(Ben zen esu lfon yl)-2-b r om o-5-m et h oxy-3-m et h ylin -
d ole (15a ) was prepared as described above for the prepara-
tion of 15b. 15a : mp 148-150 °C; 1H NMR (250 MHz, CDCl3)
δ 2.13 (s, 3H), 3.84 (s, 3H), 6.81 (d, 1H, J ) 2.3 Hz), 6.93 (dd,
1H, J ) 8.8, 2.4 Hz), 7.48-7.58 (m, 3H), 7.82 (d, 2H, J ) 8.7
Hz), 8.18 (d, 1H, J ) 8.9 Hz); MS (EI) m/ e (relative intensity)
381 (M+, 30.6), 379 (M+, 26.4), 240 (74.0), 238 (71.9), 159
(100.0). Anal. Calcd for C16H14BrNO3S‚1/2H2O: C, 49.36; H,
3.86; N, 3.60. Found: C, 49.20; H, 3.49; N, 3.34.
(S)-6-Ch lor o-5-m eth oxytr yp top h a n Eth yl Ester (21a ).
To a solution of 19 (180 mg, 0.45 mmol) in dry CH2Cl2 (10 mL)
at -78 °C was added a solution of boron tribromide (145 mg,
0.54 mmol) in dry CH2Cl2 (2 mL) dropwise under nitrogen.
The mixture was kept at -78 °C for 1 h and slowly warmed
to rt. After being stirred for 5 h, the reaction solution was
cooled to 0 °C and treated with ice-water (5 mL) and a
concentrated aqueous solution of NH4OH (1 mL) was added.
The organic layer was separated, and the aqueous layer was
extracted with CH2Cl2 (3 × 5 mL). The combined organic
layers were washed with a saturated aqueous solution of
NaHCO3 (3 mL) and brine (3 mL) and dried (Na2SO4). After
removal of solvent, the residue was purified by flash chroma-
tography on silica gel to afford 21a in 87% yield. 21a (HCl
2-Br om o-5-ch lor o-3-m eth ylin d ole (15h ) was prepared as
described above for the preparation of 15b. 15h : mp 96-98
1
°C; IR (KBr) 3000, 1648 cm-1; H NMR (250 MHz, CDCl3) δ
2.15 (s, 3H), 7.1 (dd, 1H, J ) 2 and 8.7 Hz), 7.3 (s, 1H), 7.5 (d,
1H, J ) 2 Hz), 11.8 (s, 1H, NH); MS (EI) m/ e (relative
intensity) 245 (M+, 89), 244 (M+, 48), 243 (M+, 60), 242 (35),
164 (100). This material was employed directly in a later step.
2-Br om o-3-m eth ylin d ole (15i) was prepared as described
above for the preparation of 15b. 15i: mp 91-93 °C; IR (KBr)
salt): mp 228-229 °C; [R]30 ) +8.0 (c ) 1, in CH2Cl2); IR
D
2977, 1448 cm-1 1H NMR (DMSO-d6) δ 2.09 (s, 3H), 6.95-
;
(KBr) 3279, 2932, 1740 cm-1; MS (EI) m/ e (relative intensity)
298 (M+, 14), 296 (M+, 22), 223 (17), 194 (100), 179 (19), 151
7.10 (m, 2H), 7.27 (d, 1H, J ) 7.8 Hz), 7.46 (d, 1H, J ) 7.8
Hz), 11.52 (br, 1H, D2O exchangeable); MS (EI) m/ e (relative
intensity) 211 (M+, 38.3), 209 (M+, 38.3), 130 (100.0). This
material was employed directly in a later step.
1
(100); H NMR (250 MHz, CDCl3) δ 1.22 (t, 3H, J ) 7.2 Hz),
1.70 (br, 2H, NH2), 3.00 (dd, 1H, J ) 14.5 and 7.4 Hz), 3.20
(dd, 1H, J ) 14.2 and 5.1 Hz), 3.78 (dd, 1H, J ) 7.4 and 5.2
Hz), 3.90 (s, 3H), 4.15 (q, 2H, J ) 7.2 Hz), 6.95 (d, 1H, J ) 2.2
Hz), 7.07 (s, 1H), 7.32 (s, 1H), 8.05 (br, 1H); HRMS for
C14H17N2O3Cl calcd 296.0927, found 296.0923.
(3S,6R)-3-((1-(ter t-Bu tyloxyca r bon yl)-6-ch lor o-5-m eth -
oxy-3-in d oyl)m e t h yl)-3,6-d ih yd r o-6-isop r op yl-2,5-d i-
eth oxyp yr a zin e (17). To a solution of 3(R)-isopropyl-2,5-
diethoxypyrazine25,36 (6.8 g, 0.032 mol) in THF (200 mL) was
added n-butyllithium (2.5 M in hexane, 12.83 mL, 0.032 mol)
at -78 °C under nitrogen. The solution which resulted was
stirred at -78 °C for 30 min after which a solution of 14g (10
g, 0.026 mol) in THF (50 mL) under nitrogen was added
dropwise. After the mixture was allowed to stir at -78 °C for
20 h, the reaction solution was slowly warmed to rt and treated
with a saturated aqueous solution of (NH4)2CO3 (10 mL). Most
of the solvent was removed under reduced pressure, and the
residue which resulted was treated with diethyl ether to give
two layers. The organic layer was separated, and the aqueous
layer was extracted with diethyl ether (3 × 50 mL). The
combined organic layers were washed with brine and dried
(Na2SO4). The solvent was removed under reduced pressure
(S)-6-Ch lor o-5-h yd r oxytr yp top h a n Eth yl Ester (21b).
To a solution of 19 (180 mg, 0.45 mmol) in dry CH2Cl2 (10 mL)
at -78 °C was added boron tribromide (1.6 mL, 1.57 mmol,
1.0 M solution in CH2Cl2) dropwise under nitrogen. The
mixture was kept at -78 °C for 1 h and slowly warmed to rt.
After being stirred for 6 h, the reaction solution was cooled to
0 °C and treated with ice-water (5 mL) and a concentrated
aqueous solution of NH4OH (3 mL) was added. The organic
layer was separated, and the aqueous layer was extracted with
CH2Cl2 (3 × 10 mL). The combined organic layers were
washed with a saturated aqueous solution of NaHCO3 (10 mL)
and brine (10 mL) and dried (Na2SO4). After removal of
solvent, the residue was purified by flash chromatography on
silica gel (CHCl3/MeOH/aqueous NH4OH ) 25:10:1) to afford
21b in 82% yield. 21b: mp 80-81 °C; [R]30 ) +18.6 (c ) 1.4,
D
in CH2Cl2); IR (KBr) 3350, 1725, 1432 cm-1
;
1H NMR (250
(36) Hamaker, L. K. Ph.D. Thesis, University of Wisconsin-
Milwaukee, 1995.
MHz, CDCl3) δ 1.28 (t, 3H, J ) 7.1 Hz), 2.60-2.82 (br, 3H),

Bromination of 3-Methylindoles with NBS
J . Org. Chem., Vol. 62, No. 21, 1997 7455
3.01 (dd, 1H, J ) 14.2 and 7.1 Hz), 3.18 (dd, 1H, J ) 14.3 and
5.3 Hz), 3.79 (dd, 1H, J ) 7.1 and 5.2 Hz), 4.13 (q, 2H, J ) 7.1
Hz), 7.01 (s, 1H), 7.16 (s, 1H), 7.31 (s, 1H), 8.22 (br, 1H); MS
(EI) m/ e (relative intensity) 284 (M+, 12), 282 (M+, 22), 209
(20), 182 (40), 180 (100), 145 (15). Anal. Calcd for C18H15N2O3-
Cl: C, 63.14; H, 4.42; N 8.19. Found: C, 63.04; H, 4.91; N,
7.84.
(3.2 g, 17.6 mmol) and AIBN (100 mg) were added. The
mixture was heated at reflux for 40 min and then cooled to rt.
The succinimide produced as a byproduct was filtered off and
washed with cold CCl4 (2 × 10 mL). The filtrates were
combined, and the solvent was removed under reduced pres-
sure to afford 22b as an oil which was directly used in the
next step without further purification: IR (KBr) 2927, 1731,
1449 cm-1; 1H NMR (250 MHz, CDCl3) δ 1.69 (s, 9H), 4.66 (s,
2H), 7.28 (t, 1H, J ) 7.5 Hz), 7.51 (t, 1H, J )7.5 Hz), 7.58 (d,
1H, J ) 7.5 Hz), 7.68 (d, 1H, J ) 7.6 Hz); MS (EI) m/ e (relative
intensity) 377 (M+, 2), 375 (M+, 4), 373 (M+, 2), 208 (50), 167
(30), 149 (100), 128 (32).
6-Ch lor o-5-h yd r oxy-L-tr yp top h a n (21c). To a solution
of tryptophan ethyl ester 19 (0.52 g, 1.31 mmol) in dry CH2-
Cl2 (18 mL) was added a solution of boron tribromide (1.64 g,
6 mmol) in dry CH2Cl2 (5 mL) dropwise at -78 °C under
nitrogen. The mixture was kept at -78 °C for 1 h and then
slowly warmed to rt. After 24 h, the reaction solution was
cooled to 0 °C and treated with ice water (5 mL). The aqueous
layer was separated and washed with CH2Cl2 (2 × 5 mL), and
its pH was adjusted with a dilute aqueous solution of NH4OH
to a final pH ∼4-5. The water was removed under reduced
pressure. The residue which remained was purified by flash
chromatography on silica gel (CHCl3/MeOH/concentrated aque-
ous NH4OH, 20/15/1.5) to afford 21c (0.26 g, 80%) as a white
(3S,6R)-3-((1-(ter t-Bu tyloxyca r bon yl)-2-br om o-5-m eth -
oxy-3-in d oyl)m e t h yl)-3,6-d ih yd r o-6-isop r op yl-2,5-d i-
eth oxyp yr a zin e (24a ) a n d (3R,6R)-3-((1-(ter t-bu tyloxy-
ca r bon yl)-2-br om o-5-m eth oxy-3-in d oyl)m eth yl)-3,6-d ih y-
d r o-6-isop r op yl-2,5-d ieth oxyp yr a zin e (24c). To a solution
of 3(R)-isopropyl-2,5-diethoxypyrazine (3.0 g, 14 mmol) in THF
(100 mL) was added n-butyllithium (2.5 M in hexane, 5.6 mL,
14 mmol) at -78 °C under nitrogen. The solution which
resulted was stirred at -78 °C for 30 min after which a
solution of 1-(tert-butyloxycarbonyl)-2-bromo-3-(bromomethyl)-
5-methoxyindole (22a ) (5 g, 12 mmol) in THF (20 mL) was
added dropwise under nitrogen. After the mixture was allowed
to stir at -78 °C for 20 h, the reaction solution was slowly
warmed to rt and treated with a saturated aqueous solution
of NaHCO3 (30 mL). Most of the solvent was removed under
reduced pressure, and the residue which resulted was treated
with diethyl ether to give two layers. The organic layer was
separated, and the aqueous layer was extracted with diethyl
ether (3 × 30 mL). The combined organic layers were washed
with brine and dried (Na2SO4). The solvent was removed
under reduced pressure to afford a mixture of 24a and 24c
(92/8) as an oil which was separated by flash chromatography
on silica gel (hexane/ethyl acetate, 10/1). 24a : IR (KBr) 2968,
solid: mp 275-280 °C dec; [R]30 ) -3.0 (c ) 1, in H2O); IR
D
(KBr) 3127, 3025, 1660 cm-1
;
1H NMR (CD3OD) δ 3.10 (dd,
1H, J ) 15.4, 9.3 Hz), 3.42 (dd, 1H, J ) 15.4, 3.9 Hz), 3.82
(dd, 1H, J ) 9.2, 4.0 Hz), 4.61-5.12 (br, 5H), 7.18 (br, 2H),
7.33 (s, 1H); MS (EI) m/ e (relative intensity) 256 (M+, 5), 254
(M+, 18), 208 (7), 180 (100), 145 (15), 116 (12); HRMS for
C11H11N2O3Cl calcd 254.0458, found 254.0458.
5-Meth oxytr yp top h a n (20). The experimental procedure
for the preparation of 20 was reported in a previous paper.26
1-(ter t-Bu tyloxyca r bon yl)-2-br om o-3-(br om om eth yl)-
5-m eth oxyin d ole (22a ). To a solution of 1-(tert-butyloxy-
carbonyl)-5-methoxy-3-methylindole 13b (7.1 g, 27.2 mmol) in
CCl4 (100 mL) was added N-bromosuccinimide (5.4 g, 30
mmol). The reaction solution was heated to reflux for 3 h to
afford 1-(tert-butyloxycarbonyl)-2-bromo-5-methoxy-3-meth-
ylindole (15b) as determined by the examination of the 1H
NMR spectrum. The 2-bromo-3-methylindole was gently
heated at reflux after which N-bromosuccinimide (5.4 g, 30
mmol) and AIBN (50 mg) were added. After 2-5 min, another
portion of AIBN (50 mg) was added and the reaction mixture
was kept at reflux for 40 min. The reaction solution was
allowed to cool to rt. The succinimide which resulted was
removed by filtration and washed with CCl4 (2 × 10 mL). The
combined filtrates were concentrated under reduced pressure
to afford 22a as a brown solid (9.45 g, 83%): mp 91-92 °C;
1H NMR (250 MHz, CDCl3) δ 1.71 (s, 9H), 3.88 (s, 3H), 4.67
(s, 2H), 6.93 (dd, 1H, J ) 2.5 and 9.1 Hz), 7.02 (d, 1H, J ) 2.5
Hz), 7.99 (d, 1H, J ) 9.1 Hz); MS (EI) m/ e (relative intensity)
421 (M+, 5.1), 419 (M+, 13.4), 417 (M+, 5.7), 240 (100), 238
(94.0), 224 (24.5), 222 (24.7), 115 (65.3). This material was
used in a later step without further purification.
1-(ter t-Bu tyloxycar bon yl)-2-br om o-3-m eth ylin dole (23).
To a solution of 3-methylindole 12c (6.65 g, 50 mmol) in CCl4
(100 mL) was added N-bromosuccinimide (9.29 g, 51 mmol).
The mixture was heated to reflux for 30 min. The reaction
solution was allowed to cool to rt. The succinimide obtained
was filtered off and washed with cold CCl4 (2 × 10 mL). The
filtrates were combined, and the solvent was removed under
reduced pressure to afford a brownish residue which was taken
up in dry CH3CN (150 mL). To the CH3CN solution were
added di-tert-butyl dicarbonate (11 g, 50 mmol) and DMAP
(0.3 g, 2.5 mmol) at rt. After the mixture was stirred at rt for
30 min, ethyl acetate (200 mL) and an aqueous solution of 2
N HCl (50 mL) were added to the mixture. The organic layer
was separated, washed with brine (30 mL), and dried (Na2-
SO4). The solvent was removed under reduced pressure. The
residue was purified by flash chromatography (hexane/ethyl
1
1733, 1673 cm-1; H NMR (250 MHz, CDCl3) δ 0.63 (d, 3H, J
) 6.8 Hz), 0.97 (d, 3H, J ) 6.8 Hz), 1.16 (t, 3H, J ) 7.1 Hz),
1.26 (t, 3H, J ) 7.1 Hz), 1.66 (s, 9H), 2.21 (m, 1H), 2.90 (dd,
1H, J ) 8.2 and 14.0 Hz), 3.27 (dd, 1H, J ) 4.7 and 14.0 Hz),
3.73 (t, 1H, J ) 3.3 Hz), 3.81 (s, 3H), 3.83-4.25 (m, 5H), 6.83
(dd, 1H, J ) 2.7 and 9.2 Hz), 6.98 (d, 1H, J ) 2.3 Hz), 7.91 (d,
1H, J ) 9.1 Hz); 13C NMR (62.90 MHz, CDCl3) δ 14.3, 16.6,
19.1, 28.2, 31.1, 31.4, 55.7, 60.5, 60.6, 60.8, 84.4, 102.3, 111.0,
112.5, 116.0, 120.4, 130.5, 131.2, 149.2, 155.8, 162.9, 163.7;
MS (EI) m/ e (relative intensity) 551 (M+, 10), 549 (M+, 10),
318 (20), 238 (70), 169 (72), 141 (100). This material was used
in the next experiment without further purification. 24c: IR
(KBr) 2955, 1725, 1684, 1452 cm-1; 1H NMR (250 MHz, CDCl3)
δ 0.79 (d, 3H, J ) 6.8 Hz), 1.03 (d, 3H, J ) 6.8 Hz), 1.17 (t,
3H, J ) 7.1 Hz), 1.22 (t, 3H, J ) 7.1 Hz), 1.66 (s, 9H), 2.22 (m,
1H), 2.88 (dd, 1H, J ) 8.2 and 14.0 Hz), 3.26 (dd, 1H, J ) 5.0
and 14.0 Hz), 3.71 (t, 1H, J ) 3.2 Hz), 3.82 (s, 3H), 3.83-4.28
(m, 5H), 6.84 (dd, 1H, J ) 2.6 and 9.1 Hz), 6.99 (d, 1H, J )
2.4 Hz), 7.92 (d, 1H, J ) 9.2 Hz); 13C NMR (75 MHz, CDCl3)
δ 14.2, 14.3, 17.8, 19.6, 28.2, 32.0, 55.7, 55.7, 60.6, 60.7, 61.2,
84.4, 102.0, 110.5, 112.6, 116.1, 120.6, 130.4, 131.4, 149.2,
155.8, 162.7, 163.3.
(S)-1-(ter t-Bu tyloxyca r bon yl)-2-br om o-5-m eth oxytr yp -
top h a n Eth yl Ester (25a ). To a solution of pyrazine 24a (5
g, 9.1 mmol) in THF (50 mL) at 0 °C was added an aqueous
solution of 2 N HCl (25 mL). The mixture was allowed to
warm to rt, stirred for 40 min, and poured into a cold aqueous
solution of NH4OH (final pH ∼9). The solution which resulted
was concentrated in vacuo, and CH2Cl2 (30 mL) was added.
The aqueous layer was extracted with CH2Cl2 (2 × 30 mL).
The combined organic layers were washed with brine and dried
(Na2SO4). After removal of solvent under reduced pressure,
the valine ethyl ester which resulted from hydrolysis of the
chiral auxiliary was separated by high-vacuum distillation to
be reused. The residue which remained was purified by flash
chromatography on silica gel (ethyl acetate/hexane, 1/4, fol-
lowed by ethyl acetate) to afford 25a (3.6g, 92%) as an oil (HCl
acetate, 6/1) to afford 23 as an oil: IR (KBr) 2975, 1734 cm-1
;
1H NMR (250 MHz, CDCl3) δ 1.67 (s, 9H), 2.25 (s, 3H), 7.24
(m, 2H), 7.42 (d, 1H, J )7.5 Hz), 8.05 (d, 1H, J ) 7.5 Hz); MS
(EI) m/ e (relative intensity) 311 (M+, 43), 309 (M+, 43), 253
(34), 236 (22), 209 (100), 130 (57). The material was employed
directly in a later step.
salt): mp 116-120 °C dec; IR (KBr) 2984, 1728, 1616 cm-1
;
1-(ter t-Bu tyloxycar bon yl)-2-br om o-3-(br om om eth yl)in -
d ole (22b). A solution of 23 (5.1 g, 16.0 mmol) in CCl4 (100
mL) was heated to reflux after which the N-bromosuccinimide
[R]27D ) +12.1 (c ) 2.0, in CH3OH); 1H NMR (250 MHz, CDCl3)
δ 0.98 (t, 3H, J ) 7.0 Hz), 1.31 (s, 9H), 3.42 (m, 1H), 3.61 (m,
1H), 3.80 (s, 3H), 3.99 (m, 2H), 4.39 (br, 1H), 6.81 (dd, 1H, J

7456 J . Org. Chem., Vol. 62, No. 21, 1997
Liu et al.
) 9.3, 2.1 Hz), 7.25 (d, 1H, J ) 1.7 Hz), 7.89 (d, 1H, J ) 9.2
Hz), 9.05 (br, 3H); MS (EI) m/ e (relative intensity) 442 (M+,
4), 440 (M+, 5), 361 (10), 305 (23), 238 (100), 187 (25), 149 (50).
Anal. Calcd for C19H25N2O5Br: C, 51.81; H, 5.73; N 6.36.
Found: C, 51.90; H, 6.01; N, 6.12.
same procedure employed earlier for the synthesis of 24a and
24c. 24b: IR (KBr) 2989, 1730, 1671 cm-1
;
1H NMR (500
MHz, CDCl3) δ 0.76 (d, 3H, J ) 6.9 Hz), 1.03 (d, 3H, J ) 6.6
Hz), 1.18 (t, 3H, J ) 7.1 Hz), 1.23 (t, 3H, J ) 6.9 Hz), 1.68 (s,
9H), 2.25 (m, 1H), 2.97 (dd, 1H, J ) 8.6 and 14.0 Hz), 3.36
(dd, 1H, J ) 4.8 and 14.0 Hz), 3.85 (t, 1H, J ) 4.1 Hz), 3.90-
4.29 (m, 5H), 7.19 (t, 1H, J ) 7.5 Hz), 7.25 (t, 1H, J ) 7.7 Hz),
7.53 (d, 1H, 7.7 Hz), 8.05 (d, 1H, J ) 8.3 Hz); MS (EI) m/ e
(relative intensity) 521 (M+, 8), 519 (M+, 10), 440 (70), 338
(85), 208 (90), 169 (100), 141 (87). This material was employed
directly in the next step without further purification. 24d :
IR (KBr) 2978, 1720, 1681 cm-1; 1H NMR (500 MHz, CDCl3) δ
0.75 (d, 3H, J ) 6.9 Hz), 1.01 (d, 3H, J ) 6.6 Hz), 1.17 (t, 3H,
J ) 7.1 Hz), 1.22 (t, 3H, J ) 6.9 Hz), 1.66 (s, 9H), 2.23 (m,
1H), 2.93 (dd, 1H, J ) 8.6 and 14.0 Hz), 3.30 (dd, 1H, J ) 4.8
and 14.0 Hz), 3.84 (t, 1H, J ) 4.1 Hz), 3.90-4.29 (m, 5H), 7.18
(t, 1H, J ) 7.5 Hz), 7.23 (t, 1H, J ) 7.7 Hz), 7.51 (d, 1H, 7.7
Hz), 8.02 (d, 1H, J ) 8.3 Hz).
2-Br om o-5-m eth oxy-L-tr yp top h a n Eth yl Ester (26a ).
To a solution of tryptophan ethyl ester 25a (0.4 g, 0.9 mmol)
in dry CH2Cl2 (10 mL) was added a solution of boron tribromide
(1 mL, 1.0 M solution in CH2Cl2) in dry CH2Cl2 (5 mL) dropwise
at -78 °C under nitrogen. The mixture was kept at -78 °C
for 1 h and then slowly warmed to rt. After 2 h, the reaction
solution was cooled to 0 °C and treated with a dilute aqueous
solution of NH4OH to a final pH ∼8. The aqueous layer was
separated and extracted with CH2Cl2 (3 × 50 mL). The organic
layers were combined, washed with brine (30 mL), and dried
(Na2SO4). The solvent was removed under reduced pressure.
The residue was purified by a wash column (silica gel, hexane/
ethyl acetate, 1/1) to afford 26a as an oil (81%). 26a (HCl
salt): mp 106-110 °C dec; IR (KBr) 2966, 1738, 1685 cm-1
;
(S)-1-(ter t-Bu tyloxyca r bon yl)-2-br om otr yp top h a n Eth -
yl Ester (25b) was prepared from 24b using the same
procedure as described for the synthesis of 25a . 25b (HCl
[R]27 ) +10.00 (c ) 1.0, in CH3OH); 1H NMR (250 MHz,
D
DMSO-d6) δ 0.99 (t, 3H, J ) 7.1 Hz), 3.10 (m, 1H), 3.21 (m,
1H), 3.82 (m, 1H), 3.83 (s, 3H), 4.05 (m, 2H), 6.78 (dd, 1H, J )
8.5, 2.3 Hz), 7.08 (d, 1H, J ) 1.6 Hz), 7.20 (d, 1H, J ) 8.2 Hz),
8.60 (br, 3H, D2O exchangeable), 11.7 (br, 1H, D2O exchange-
able).
salt): mp 88-90 °C; [R]27 ) +17.20 (c ) 1.0, in CH3OH); IR
D
(KBr) 3396, 3191, 2979, 1738, 1450 cm-1; 1H NMR (250 MHz,
DMSO-d6) δ 0.91 (t, 3H, J ) 7.0 Hz), 1.63 (s, 9H), 3.09 (m,
1H), 3.19 (m, 1H), 3.41 (m, 1H), 3.96 (q, 2H, J ) 7.1 Hz), 7.28
(t, 1H, J ) 7.6 Hz), 7.34 (t, 1H, J ) 7.6 Hz), 7.76 (d, 1H, J )
7.6 Hz), 7.99 (d, 1H, J ) 7.6 Hz), 8.87 (br, 3H, D2O exchange-
able); HRMS for C18H23N2O4Br calcd 410.0841, found 410.0843.
(S)-2-Br om otr yp top h a n eth yl ester (26b) was prepared
following the procedure employed for the synthesis of 26a . 26b
2-Br om o-5-h yd r oxy-L-tr yp top h a n Eth yl Ester (26c).
Using a similar procedure to that described above for the
preparation of 26a , the removal of the tert-butyloxycarbonyl
and methyl moieties of 25a was accomplished with 3 equiv of
boron tribromide to afford 26c (79%) as a brown-yellow solid.
26c: mp 164-170 °C dec; IR (KBr) 3295, 2986, 1724 cm-1
;
(HCl salt): mp 150-152 °C; [R]27 ) +20.80 (c ) 2.0, in CH3-
D
[R]27 ) +27.40 (c ) 1.0, in CH3OH); 1H NMR (250 MHz,
OH); IR (KBr) 3392, 3193, 2980, 2919, 1736 cm-1
;
1H NMR
D
DMSO-d6) δ 1.02 (t, 3H, J ) 7.1 Hz), 2.10 (br, 2H, D2O
exchangeable), 2.75 (dd, 1H, J ) 14.1, 7.4 Hz), 2.87 (dd, 1H, J
) 14.1, 7.3 Hz), 3.54 (t, 1H, J ) 7.0 Hz), 3.95 (q, 2H, J ) 7.2
Hz), 6.58 (dd, 1H, J ) 8.7, 2.2 Hz), 6.78 (d, 1H, J ) 2.0 Hz),
7.04 (d, 1H, J ) 8.5 Hz), 8.70 (s, 1H, D2O exchangeable), 11.29
(s, 1H, D2O exchangeable). MS (EI) m/ e (relative intensity)
328 (M+, 25), 326 (M+, 31), 246 (50), 224 (100), 173 (20), 146
(35). Anal. Calcd for C13H15N2O3Br: C, 47.72; H, 4.62; N, 8.56.
Found: C, 48.02; H, 4.56; N, 8.79.
(250 MHz, DMSO-d6) δ 0.93 (t, 3H, J ) 7.2 Hz), 3.12 (m, 1H),
3.24 (m, 1H), 3.29 (m, 1H), 4.01 (m, 2H), 7.05 (t, 1H, J ) 7.5
Hz), 7.11 (t, 1H, J ) 7.4 Hz), 7.30 (d, 1H, J ) 7.9 Hz), 7.53 (m,
1H), 8.60 (br, 3H, D2O exchangeable), 11.85 (s, 1H, D2O
exchangeable); MS (EI) m/ e (relative intensity) 312 (M+, 21),
310 (M+, 25), 157 (85), 130 (95), 129 (75), 108 (10); HRMS for
C13H15N2O2Br calcd 310.0317, found 310.0308. Anal. Calcd
for C13H15N2O2Br: C, 50.18; H, 4.86; N, 9.00. Found: C, 50.46;
H, 4.70; N, 8.79
(3S,6R)-3-((1-(ter t-Bu tyloxycar bon yl)-2-br om o-3-in doyl)-
m et h yl)-3,6-d ih yd r o-6-isop r op yl-2,5-d iet h oxyp yr a zin e
(24b) a n d (3R,6R)-3-((1-(ter t-bu tyloxyca r bon yl)-2-br om o-
3-in d oyl)m et h yl)-3,6-d ih yd r o-6-isop r op yl-2,5-d iet h oxy-
p yr a zin e (24d ) were prepared in a ratio of 90:10 using the
Ack n ow led gm en t. This work was supported by a
grant from the NIMH and the Graduate School (UWM).
J O971067G