Novel strategies for the solid phase synthesis of substituted indolines and indoles

Article abstract of DOI:10.1016/S0968-0896(02)00386-3

Using a polymer-bound selenenyl bromide resin, o-allyl and o-prenyl anilines were cycloaded to afford a series of solid-supported indoline and indole scaffolds. These scaffolds were then functionalized and cleaved via four distinct methods, namely traceless reduction, radical cyclization, radical rearrangement, and oxidative elimination, to afford 2-methyl indolines, polycyclic indolines, 2-methyl indoles, and 2-propenyl indolines, respectively. A number of small combinatorial libraries of compounds reminiscent of certain designed ligands of biological interest were constructed demonstrating the potential utility of the developed methodology to chemical biology studies and the drug discovery process.

Full text of DOI:10.1016/S0968-0896(02)00386-3

Bioorganic & Medicinal Chemistry 11 (2003) 465–476
Novel Strategies for the Solid Phase Synthesis of Substituted
Indolines and Indoles
K. C. Nicolaou,a,b,* A. J. Roecker,a Robert Hughes,a Ruben van Summeren,a
Jeffrey A. Pfefferkorna and Nicolas Winssingera
aDepartment of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, CA 92037, USA
bDepartment of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
Received 10 June 2002; accepted 29 July 2002
Abstract—Using a polymer-bound selenenyl bromide resin, o-allyl and o-prenyl anilines were cycloaded to afford a series ofsolid-
supported indoline and indole scaffolds. These scaffolds were then functionalized and cleaved via four distinct methods, namely
traceless reduction, radical cyclization, radical rearrangement, and oxidative elimination, to afford 2-methyl indolines, polycyclic
indolines, 2-methyl indoles, and 2-propenyl indolines, respectively. A number ofsmall combinatorial libraries ofcompounds remi-
niscent ofcertain designed ligands ofbiological interest were constructed demonstrating the potential utility ofthe developed
methodology to chemical biology studies and the drug discovery process.
# 2002 Elsevier Science Ltd. All rights reserved.
Introduction
and the 2-propenyl indoline templates, were selected as
initial goal structures as it was envisaged that they could
be accessed from a common resin-bound indoline inter-
mediate 2 (Fig. 2). Herein, we describe the design and
production ofcombinatorial libraries ofsubstituted
indolines and indoles using a novel selenium-based
linking strategy.
Combinatorial chemistry has become an important tool
in both drug discovery and chemical biology studies and
its continued success is dependent, in part, on further
advances in solid phase organic synthesis (SPOS).1 Our
laboratory has been engaged in the development of
novel solid phase linking strategies and chemical tech-
nologies aimed at the construction ofdiscovery-oriented,
natural product-like libraries.2 Toward this end, several
natural product-like templates have been tethered to a
solid support utilizing an intramolecular, selenium-
mediated cycloaddition procedure. Encouraged by our
success in developing chemistry and technology to pro-
duce natural product-like libraries ofoxygen-containing
heterocycles and carbocyclic frameworks3 and due to
the potential utility ofsuch libraries in chemical biology
investigations,4 we sought to expand the scope ofthis
selenium-based solid phase chemistry to include nitro-
gen-containing heterocycles. The indoline and indole
frameworks are embedded in a wide range of natural
products and designed compounds with varied biologi-
cal activities (see Fig. 1 for selected examples).5 Four
types ofindoline and indole templates, namely the
2-methyl indoline, polycyclic indoline, 2-methyl indole,
Results and Discussion
Library design and synthetic strategy to substituted
indolines and indoles
Recently, we reported a selenium-based approach for
the solid phase combinatorial synthesis ofbenzopyran-
containing natural products and analogues thereofuti-
lizing a practical cycloloading strategy.3a,b Given the
versatility ofthis approach, we sought to extend it
toward the solid phase synthesis ofother heterocycles. It
was projected that substituted o-allyl anilines (1, R1=H,
Fig. 2) might be cycloloaded onto a polystyrene-derived
selenenyl bromide resin6 via a 5-exo-trig cyclization to
afford resin-bound indoline scaffolds (2, R1=H). Ela-
boration of 2 (R1=H) would provide structures such as
3 (R1=H) that could be tracelessly cleaved providing
access to 2-methyl indolines (5), a structural class from
which several drug candidates have emerged, including
antineoplastic sulfonamides,5c 5-hydroxytryptamine
*Corresponding author. Tel.: +1-858-784-2400; fax: +1-858-784-2469;
e-mail: kcn@scripps.edu
0968-0896/03/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(02)00386-3

466
K. C. Nicolaou et al. / Bioorg. Med. Chem. 11 (2003) 465–476
receptor antagonists (5-HT3),7a and muscarine receptor
agonists and antagonists.7b Moreover, it was expected
that the ability ofthis selenium tether to generate a
carbon-centered radical upon cleavage might be
exploited to create additional complexity in the target
structure concomitant with release. Specifically, ifan
intramolecular radical acceptor could be positioned in
proximity to this radical (i.e., as in 4, Fig. 2), then rela-
tively complex polycyclic indolines (6) could be con-
structed in short order.8 In order to create further
diversity during the cleavage operation, it was reasoned
that ifresin-bound indoline 2 (R1=H) was functiona-
lized to afford 7 and then treated with a radical initiator
in the absence ofa quenching agent (i.e., n-Bu3SnH), a
radical rearrangement may ensue leading to substituted
indoles (9).9 Finally, it was thought that o-prenyl ani-
lines (1, R1=Me) could be cyclized in a similar mode to
their allyl cousins via 5-exo-trig fashion to give indoline
scaffolds 2 (R1=Me). These scaffolds could then be fur-
ther functionalized to afford 8 and the selenium tether
could be cleaved under oxidative conditions to produce
the targeted 2-propenyl indoline structure (10). Below we
describe the implementation ofthis strategy to the con-
struction ofa series ofsubstituted indolines and indoles.
Loading of o-allyl anilines onto solid support and process
development
In order to efficiently access indoline scaffolds 2, it was
first necessary to define conditions for the cycloloading
of o-allyl anilines onto the resin.10 Preliminary solution
phase studies with o-allyl aniline (11, Table 1) revealed
that such unprotected anilines could smoothly undergo
a selenium-mediated cyclization with PhSeBr in the
presence ofsuitable Lewis acid catalysts such as AgOTf
or SnCl4. Encouraged by this result, we attempted the
corresponding reaction on solid phase. Hence, treat-
ment ofa suspension ofthe selenenyl bromide resin and
aniline 11 (3.0 equiv) in the presence ofSnCl
(3.0
4
equiv) at ꢀ20 ꢁC in CH2Cl2 resulted in rapid resin
decolorization signaling attachment ofthe substrate
onto the solid support. Subsequent treatment ofthe
resulting resin with n-Bu3SnH (2.5 equiv) and AIBN
(0.5 equiv) at 90 ꢁC in toluene followed by polarity-
11
based removal ofthe reaction by-products
indoline 18 in 87% overall yield (for loading and sub-
afforded
1
sequent cleavage) and 89% purity (determined by H
Figure 1. Biologically active polycyclic indolines, 2-methyl indolines
and 2-methyl indoles.
NMR). As shown in Table 1, a series ofuf nctionalized
anilines were then prepared and tested for loading.12
Substrates 11–17, bearing alkyl substituents or halo-
gens, underwent facile loading under these conditions
Table 1. Selenium-mediated loading ofsubstituted o-allyl anilines
Entry Aniline R1
R2
R3 R4 Product Temp Time Purity
(ꢁC)
(h) (%)a
1
2
3
4
5
6
7
8
11
12
13
14
15
16
17
18
19
20
21
H
H
Me
H
H
H
H
H
H
H
H
H
Me
H
t-Bu
F
Cl
Br
CN
CO2Me
NO2
OMe
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
22
23
24
25
26
27
28
29
30
31
32
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
0
0
0
ꢀ20
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1.0
1.0
1.0
0.5
89
85
92
92
86
94
89
95
95
n/a
n/a
9
10
11
H
Reagents and reaction conditions: 1.0 equiv ofselenenyl bromide resin
(0.75 mmol/g), 3.0 equiv of o-allyl aniline, 3.0 equiv ofSnCl
.
4
AIBN=2,20-azobisisobutyronitrile.
aPurities estimated by cleavage (n-Bu3SnH, AIBN, 90 ꢁC), polarity-
based purification, and 1H NMR analysis. Loading ranged from 54–
87% as determined by weight ofcleavage product.
Figure 2. General strategy for the solid phase cycloloading, function-
alization, and cleavage ofsubstituted indolines and indoles.

K. C. Nicolaou et al. / Bioorg. Med. Chem. 11 (2003) 465–476
467
(ꢀ20 ꢁC, 0.5 h), whereas those with electron with-
drawing groups (18 and 19) required slightly modified
conditions (0 ꢁC, 1 h). The only substrates from those
tested which failed to load were 4-nitro aniline (20) and
4-methoxy aniline (21).
(33, COCl2) which were subsequently reacted with var-
ious amines (R2NHx) to afford ureas (34). When dia-
mines such as piperazine (38) were utilized, the resulting
secondary amine could be further derivatized by cou-
pling with carboxylic acids (R3CO2H). All ofthe
resulting indolines (34 or 36) were tracelessly cleaved
under reducing conditions to produce compounds of
type 35 or 37. The parallel application ofthis sequence
to indoline scaffolds 22, 23, and 29, amines 38–40, and
carboxylic acids 41–43 resulted in the formation of a
nine-membered library of2-methyl indolines ( 44–52) in
reasonable yields and purity (see Scheme 1).
Library construction
With resin-bound indolines 22–30 (Table 1) now in
hand, we set out to explore their aforementioned appli-
cations. First, we undertook the solid phase synthesis of
a collection of2-methyl indolines resembling previously
reported 5-HT3 receptor antagonists7a in order to
demonstrate how the current linking strategy might be
employed in combinatorial synthesis. The adopted syn-
thetic strategy is outlined at the top of Scheme 1. Thus,
resin-bound indolines were converted to acyl chlorides
As stated above, our second goal was to develop a
diversity-building cleavage protocol whereby the sele-
nium tether would be utilized as a progenitor to a car-
bon-centered radical which could engage a proximal
functionality to afford polycyclic indolines. Hence, the
secondary nitrogen ofindoline 22 (Scheme 2) was cou-
pled to a series ofolefinic radical acceptors via either
amide or alkyl linkages to form derivatives of type 53
which could be released with concomitant cyclization to
provide polycyclic indolines oftype 54. For example,
DCC coupling ofindoline 22 with 1-cyclopentene-1-
carboxylic acid (55) afforded the corresponding amide
which was then suspended in toluene at 90 ꢁC and a
solution of n-Bu3SnH and AIBN was slowly added over
Scheme 2. Radical-based release and cyclization producing polycyclic
indolines. Reagents and reaction conditions: (a) Coupling produre A:
10.0 equiv ofacid, 10.0 equiv ofDCC, 1.3 equiv of4-DMAP, CH 2Cl2,
25 ꢁC, 24 h; Coupling procedure B: 10.0 equiv ofalkenyl bromide, 20.0
equiv ofNaH, DMF, 60 ꢁC, 48 h; (b) 4.0 equiv of n-Bu3SnH, 1.3 equiv
ofAIBN, toluene, 90 ꢁC, 4 h. aProducts obtained as single diaster-
eomers with relative stereochemistry shown as determined by 1H
NMR and ROESY analysis unless otherwise noted. bIsolated yield of
chromatographically pure material over three steps based on an esti-
mated resin loading of0.75 mmol/g. Yield in parentheses reefrs to
average yield per chemical transformation.
Scheme 1. Parallel synthesis ofsubstituted 2-methyl indolines.
Reagents and reaction conditions: (a) 27.0 equiv ofCOCl 2, CH2Cl2,
0 ꢁC, 1 h; (b) 10.0 equiv R2NHx, 27.0 equiv ofEt 3N, CH2Cl2, 25 ꢁC, 12
h; (c) 4.0 equiv of n-Bu3SnH, 1.3 equiv ofAIBN, toluene, 90 ꢁC, 2 h;
(d) 10.0 equiv ofR 3CO2H, 10.0 equiv ofDCC, 1.3 equiv of4-DMAP,
CH2Cl2,
25 ꢁC,
16
h.
DCC=1,3-dicyclohexylcarbodiimide.
4-DMAP=4-dimethylaminopyridine. aIsolated yields ofchromato-
graphically pure material over four or five steps. Yield in parentheses
refers to average yield per chemical transformation.

468
K. C. Nicolaou et al. / Bioorg. Med. Chem. 11 (2003) 465–476
a 4 h interval. To our delight, tetracycle 60 was released
as a single diastereomer in 26% yield over three steps.
Coupling of 22 with 1-cyclohexene-1-carboxylic acid
(56) and trans-cinnamic acid (57) followed by similar
cleavage from the solid support afforded tetracycle 61
and tricycle 62 in moderate yields (36 and 13%, respec-
tively) over three steps. In addition, alkylation (NaH,
DMF, 60 ꢁC) ofindoline 22 with either allyl or crotyl
bromide (58 or 59) led to the formation of tricycles 63
and 64 in 18 and 19% yields, respectively.
process to produce 2-methyl indoles (9). This idea came
to fruition upon treatment of polymer-bound indoline 22
(Scheme 3) with various electrophiles to form sulfona-
mides, amides and ureas (65). These functionalized
indoline scaffolds were then treated with AIBN (3.0
equiv) in refluxing benzene to afford 2-methyl indoles
(70–75) in satisfactory yields (23–64% over three steps).
The formation of the 2-methyl indole presumably arises
via a 1,2- or 1,3-hydride shift within the initially formed
primary radical 66 (Scheme 3, structures 67 and 68,
respectively) followed by elimination of a hydrogen
radical to afford the final product.
In a final application ofthe resin-bound indoline sca-f
fold 2 (Fig. 2, R1=H), the 2-methyl indole was tar-
geted as a template for library design as it represented
an important class ofbiologically relevant ligands,
including the analgesic agent pravadoline (Fig. 1).5b It
was envisioned that exposure of 7 (Fig. 2) to an
appropriate radical initiator in the absence ofa
quenching agent could lead to a radical rearrangement
Scheme 4. Selective loading of2,2-dimethyldihydroquinoline or indo-
line scaffolds via o-prenylated anilines. Purities estimated by 1H NMR
spectroscopic analysis after oxidative cleavage (see Experimental for
details).
Table 2. Selenium-mediated cycloloading ofsubstituted o-prenyl
anilines
Entry Urethane R1
R2
R3 R4 Product Purity (%)a,b
1
2
3
4
5
78
81
82
83
84
H
Me
H
H
H
CN
H
Br
CO2Me
NO2
H
Me
H
H
H
H
H
H
H
H
80
85
86
87
88
95
95
95
95
90
Scheme 3. Radical rearrangement cleavage ofuf nctionalized indoles.
Reagents and reaction conditions: (a) acylation produre A: 10.0 equiv
ofelectrophile, 20.0 equiv of i-Pr2NEt, 1.0 equiv of4-DMAP, CH 2Cl2,
25 ꢁC, 48 h; acylation procedure B: 20.0 equiv COCl2, 20.0 equiv Et3N,
CH2Cl2, 0 ꢁC, 1 h, filter and wash, then 20.0 equiv amine, 20.0 equiv
Et3N, CH2Cl2, 25 ꢁC, 18 h; (b) 3.0 equiv AIBN, benzene, 85 ꢁC, 48 h.
aIsolated yield ofchromatographically pure material based on an esti-
mated resin loading of0.75 mmol/g. bYield in parentheses refers to
average yield per chemical transformation.
Reagents and conditions: 1.0 equiv ofselenenyl bromide resin (0.75
mmol/g), 2.0 equiv of o-prenyl aniline, 3.0 equiv ofSnCl 4.
aPurities estimated by cleavage (H2O2, THF, 25 ꢁC) and 1H NMR
analysis.
bLoading ranged from 75–95% as determined by recovery of oxida-
tively cleaved product.

K. C. Nicolaou et al. / Bioorg. Med. Chem. 11 (2003) 465–476
469
Cycloloading of o-prenyl anilines and library
construction
to undergo cyclization in a 5-exo-trig manner, this
would afford the 2-propenyl indoline substructure.
However, according to literature precedents, selenium-
mediated cyclizations of o-prenylated anilines or ure-
thanes produced either mixtures ofindoline and quino-
line or exclusively the indoline product, depending on
the reaction conditions.10b,15 Gratifyingly, after much
experimentation, it was found that the selectivity of this
cyclization (5-exo vs. 6-endo) could be modulated
through the electronic properties ofthe aniline ring and
proper derivatization ofthe aniline nitrogen as shown in
Scheme 4. Thus, treatment ofa suspension ofthe sele-
nenyl bromide resin in CH2Cl2 at 0 ꢁC with 2 equiva-
lents of4-cyano-2-prenylaniline ( 75) afforded complete
conversion to the 2,2-dimethyldihydroquinoline nucleus
(76) after 30 min, which, after oxidative cleavage, pro-
duced quinoline 77 in>95% purity. Complementary to
this result, ifthe resin was treated with the ethyl carba-
mate of4-cyano-2-prenylaniline ( 78) followed immedi-
ately by the addition oftin (IV) chloride, smooth
conversion to the 2-propenyl indoline nucleus (79) was
observed after 2 h, which, after oxidative cleavage, gave
indoline 80 in>95% purity. Unfortunately, all attempts
to cleanly functionalize the nitrogen center of the 2,2-
dimethyldihydroquinoline scaffold (76) were hampered
by the severe steric encumbrance ofthis position due to
the adjacent gem-dimethyl group as well as the dimin-
ished nucleophilicity ofthis group (only electron-defi-
cient, i.e., CN and NO2, anilines afforded clean
conversion to the quinoline nucleus). Unfortunately,
derivatization ofthe aromatic ring was complicated by
the presence ofthe unprotected nitrogen, as most
diversity building transformations attempted proved
unsuccessful in the presence of a free secondary amine.
Hence, the 2-propenyl indoline scaffold was selected for
further development as a template for library design.
In order to obtain the second indoline scaffold (2, Fig. 2,
R1=Me), it was necessary to study the cyclization of o-
prenyl anilines (1, R1=Me).13 It was reasoned that if
these substrates undergo the cyclization event in a 6-
endo-trig fashion, this would afford the 2,2-dimethyldi-
hydroquinoline nucleus, a structural class which has
received considerable attention from the pharmaceutical
industry.14 On the other hand, ifthese substrates were
As shown in Table 2, cyclization ofelectron-rich ( 81)
and electron-deficient (78 and 82–84) o-prenylated ure-
thanes afforded the tethered 2-propenyl indoline nucleus
(79 and 85–88) in good to excellent yields (75–95% after
oxidative cleavage) and greater than 90% purity. In
order to explore the utility ofthis application to library
construction, we synthesized a 12-membered library of
tetrazole-containing 2-propenyl indolines reminiscent of
the antihypertensive and diuretic agent, indapamide,5a
and the anticancer agent, both shown in Fig. 1. As
shown in Scheme 5, aryl cyanide 79 was treated with
azidotrimethyltin to form, after acidic hydrolysis, a free
tetrazole16 which was then alkylated with three alkyl
halides in the presence ofdiisopropylethylamine to
afford functionalized tetrazoles (89).17 These tetrazoles
were either cleaved directly to yield carbamates (100–
102) or transformed into ureas (90) upon exposure to
trimethylaluminum and primary amines18 followed by
oxidative cleavage (91–99).
Scheme 5. Solid phase parallel synthesis of2-propenyl indoline tetra-
zole library. Reagents and conditions: (a) 10.0 equiv ofMe 3SnN3,
PhMe, 100 ꢁC, 12 h, filter and wash, then TFA/CH2Cl2 (1:20), 25 ꢁC, 1
h; (b) 20.0 equiv R1X, 30.0 equiv of i-Pr2NEt, CH3CN, 80 ꢁC, 12 h; (c)
20.0 equiv AlMe3, 20.0 equiv amine, PhMe, 90 ꢁC, 12 h; (d) 6.0 equiv
Conclusion
ofH O2, THF, 25 ꢁC, 1 h. TFA=trifluoroacetic acid. Isolated yields
a
2
In summary, we have described the successful loading,
functionalization, and cleavage of four novel classes of
natural product-like templates, namely 2-methyl indoline,
ofchromatographically pure material based on an estimated resin
loading of0.75 mmol/g. Number in parentheses indicates average yield
per chemical transformation.

470
K. C. Nicolaou et al. / Bioorg. Med. Chem. 11 (2003) 465–476
polycyclic indoline, 2-methyl indole, and 2-propenyl
indoline using selenium-based solid phase chemistry.
These technologies may prove useful in the synthesis of
further combinatorial libraries of biologically relevant
compounds for chemical biology studies and drug
discovery purposes.
centrated. The crude product was purified by column
chromatography (silica, 5!25% EtOAc in hexanes) to
yield 2-allyl-4-chloro aniline (16) (0.65 g, 26%). All
other o-allyl aniline substrates were prepared in an
identical fashion with the following exceptions. In order
to reduce the amount of N,N-bisallyl aniline product
formed during N-allylation ofelectron rich anilines, a
sub-stoichiometric amount (0.65 equiv) ofallyl bromide
and a shorter reaction time (2 h) were used in the pre-
paration ofsubstrates 12–16 and 21. Also, since ZnCl2
failed to catalyze the amino Claisen rearrangement of
electron poor substrates 18–20, BF3ꢂOEt2 (1.0 equiv)
Experimental
General techniques
Reagents and resins were purchased at highest com-
mercial quality and used without further purification,
unless otherwise stated. Anhydrous solvents were
obtained by passing them through commercially avail-
able alumina column. All reactions were carried out
under an argon atmosphere with dry solvents under
anhydrous conditions, unless otherwise noted. Solution
phase reactions were monitored by thin layer chroma-
tography carried out on 0.25 mm E. Merck silica gel
plates (60F-254) using UV light as visualizing agent and
7% ethanolic phosphomolybdic acid or p-anisaldehyde
solution and heat as developing agents. E. Merck silica
gel (60, particle size 0.040–0.063 mm) was used for flash
column chromatography. Preparative thin-layer chro-
matography (PTLC) separations were carried out on
0.25 mm E. Merck silica gel plates (60F-254). All final
products cleaved from solid support were characterized
was used instead ofZnCl and the reaction time was
2
shortened to 2 h. Physical data for previously
unreported o-allyl anilines 12–21 are listed below:
12: Rf=0.14 (silica gel, EtOAc/hexanes 1:9); FT-IR
(neat) nmax 3364, 3341, 3076, 2915, 1632, 1504, 1435 cmꢀ1
;
1H NMR (400MHz, CDCl3) d=6.90–6.87 (m, 2H), 6.62
(d, J=7.6 Hz, 1H), 6.01–5.91 (m, 1H), 5.15–5.08 (m, 2H),
3.54 (s, 2H), 3.29 (d, J=6.2 Hz, 2H), 2.25 (s, 3H); 13C
NMR (100MHz, CDCl3) d=142.2, 136.2, 130.9, 128.3,
128.1, 124.3, 116.2, 116.1, 36.6, 20.6; HRMS calcd for
C10H13N [M+H+] 148.1121, found 148.1127.
13: Rf=0.15 (silica gel, EtOAc/hexanes 1:9); FT-IR
(neat) nmax 3444, 3366, 2917, 1620, 1579, 1457 cmꢀ1; 1H
NMR (500 MHz, CDCl3) d=6.54 (s, 1H), 6.44 (s, 1H),
5.98–5.92 (m, 1H), 5.10–5.03 (m, 2H), 3.62 (s, 2H),
3.35–3.33 (m, 2H), 2.28 (s, 3H), 2.26 (s, 3H); 13C NMR
(125 MHz, CDCl3) d=144.8, 137.1, 136.4, 135.1, 121.8,
119.4, 114.9, 114.6, 31.4, 20.9, 19.7; HRMS calcd for
C11H15N [M+H+] 162.1283, found 162.1280.
1
by H NMR and HRMS. NMR spectra were recorded
on Bruker DRX-600, AMX-500 or AMX-400 instru-
ments and calibrated using residual undeuterated sol-
vent as an internal reference. High resolution mass
spectra (HRMS) were recorded on a VG ZAB-ZSE
mass spectrometer under MALDI-FTMS conditions
with NBA as the matrix or gas chromatography–mass
spectra (GCMS) conditions. Representative procedures
for each combinatorial library synthesized are provided
below. The following abbreviations were used to explain
the multiplicities: s=singlet, d=doublet, t=triplet,
q=quartet, m=multiplet, oct=octet, quin=quintuplet,
sep=septet, sext=sextet, b=broad.
14: Rf=0.12 (silica gel, EtOAc:hexanes 1:9); FT-IR
(neat) nmax 3446, 3368, 3222, 2959, 1623, 1505, 1463
1
cmꢀ1; H NMR (400 MHz, CDCl3) d=7.13–7.08 (m,
2H), 6.77–6.71 (m 1H), 6.02–5.92 (m, 1H), 5.15–5.10 (m,
2H), 3.36 (d, J=6.4 Hz, 2H), 1.29 (s, 9H); 13C NMR
(100 MHz, CDCl3) d=152.7, 151.0, 136.1, 127.2, 124.3,
116.2, 115.6, 36.8, 34.0, 31.5; HRMS calcd for C13H19N
[M+H+] 190.1596, found 190.1593.
Preparation of o-allyl anilines 11–21
Representative procedure. Preparation of 16.19 To a
solution of4-chloro aniline (10.0 g, 78.3 mmol, 1.0
equiv) in DMF (40 mL) at 0 ꢁC was added allyl bromide
(5.77 mL, 78.3 mmol, 1.0 equiv). The solution was
warmed to room temperature and allowed to stir for 12
h. The reaction mixture was then poured into a solution
of10% NaOH (100 mL) and extracted with EtOAc
(2Â100 mL). The combined organic layers were washed
with brine (100 mL), dried over MgSO4, and con-
centrated, and the crude product was purified by col-
umn chromatography (silica, 5–10% EtOAc in hexanes)
to afford N-allyl-4-chloro aniline (3.85 g, 29%). To
fused ZnCl2 (6.10 g, 44.7 mmol, 3.0 equiv) was added a
solution of N-allyl-4-chloro aniline (2.5 g, 14.9 mmol,
1.0 equiv) in xylenes (25 mL) and the resuꢁlting hetero-
genous reaction mixture was heated to 145 C for 5.5 h.
After cooling, the reaction mixture was poured into
10% NaOH (10 mL), and extracted with EtOAc (3Â10
mL). The combined organic extracts were then washed
with brine (30 mL), dried over MgSO4, and con-
15: Rf=0.65 (silica gel, EtOAc/hexanes 1:3); FT-IR
(neat) nmax 3446, 3370, 3078, 2977, 1634, 1501, 1436
1
cmꢀ1; H NMR (400 MHz, CDCl3) d=6.81–6.75 (m,
2H), 6.65–6.62 (m, 1H), 5.98–5.88 (m, 1H), 5.18–5.08
(m, 2H), 3.57 (s, 2H), 3.28 (d, J=6.2 Hz, 2H); 13C
NMR (100 MHz, CDCl3) d=140.3, 135.1, 117.0, 116.9,
116.7, 116.5, 114.0, 113.7, 36.4; HRMS calcd for
C9H10FN [M+] 152.0875, found 152.0871.
16: Rf=0.64 (silica gel, EtOAc/hexanes 1:3); FT-IR
(neat) nmax 3458, 3379, 3218, 2976, 1622, 1490, 1415
1
cmꢀ1; H NMR (400 MHz, CDCl3) d=7.04–7.01 (m,
2H), 6.64 (dd, J=9.1, 3.0 Hz, 1H), 5.97–5.87 (m, 1H),
5.17–5.08 (m, 2H), 3.81 (s, 2H), 3.27 (d, J=6.2 Hz, 2H);
13C NMR (100 MHz, CDCl3) d=135.4, 130.2, 127.7,
117.6, 117.3, 36.6; HRMS calcd for C9H10ClN [M+]
168.0580, found 168.0583.
17: Rf=0.68 (silica gel, EtOAc/hexanes 1:3); FT-IR
(neat) nmax 3457, 3380, 3078, 2974, 1621, 1488, 1412

K. C. Nicolaou et al. / Bioorg. Med. Chem. 11 (2003) 465–476
471
cmꢀ1
;
1H NMR (400 MHz, CDCl3) d=7.18–7.15 (m,
(24.6 mg, 0.150 mmol, 1.0 equiv) were added after
which the reaction mixture was heated to 90 ꢁC for 2 h.
After cooling, the suspension was poured into a fritted
funnel and the resin was washed with CH2Cl2 (2Â10
mL). The filtrate was then concentrated and 10% HCl
(5 mL) was added, and the resulting solution was
washed with hexanes (3Â10 mL). The aqueous phase
was then neutralized with 10% NaOH and extracted
with Et2O (2Â10 mL). The combined organic layers
were washed with brine (10 mL), dried over MgSO4,
and concentrated to afford 22 (17.4 mg, 87% yield in
89% purity as estimated by 1H NMR). An identical
procedure was used for the cyclization of o-allyl anilines
12–17, while for substrates 18 and 19 the reaction time
and temperature were increased to 1 h and 0 ꢁC,
respectively.
2H), 6.61 (d, J=8.8 Hz, 1H), 5.97–5.87 (m, 1H), 5.18–
5.08 (m, 2H), 4.12 (s, 2H), 3.28 (d, J=6.2 Hz, 2H); 13C
NMR (100 MHz, CDCl3) d=134.9, 132.6, 130.2, 117.7,
116.9, 36.1; HRMS calcd for C9H10BrN [M+H+]
210.9997, found 210.9991.
18: Rf=0.20 (silica gel, EtOAc/hexanes 1:3); FT-IR
(neat) nmax 3476, 3377, 3235, 2978, 2214, 1635, 1571,
1504, 1432 cmꢀ1; 1H NMR (400 MHz, CDCl3) d=7.37–
7.33 (m, 2H), 6.70 (d, J=8.2 Hz, 1H), 5.94–5.86 (m,
1H), 5.22–5.10 (m, 2H), 4.60 (s, 2H), 3.29 (d, J=6.2
Hz, 2H); 13C NMR (100 MHz, CDCl3) d=134.4,
134.3, 132.1, 132.1, 124.9, 124.8, 120.1, 117.7, 116.1,
35.9; ESMS calcd for C10H10N2 [M+H+] 159, found
159.
19: Rf=0.45 (silica gel, EtOAc/hexanes 1:3); FT-IR
(neat) nmax 3475, 3375, 3234, 2948, 1697, 1632, 1436,
Solid phase synthesis of 2-methyl indolines 44–52
1277 cmꢀ1
;
1H NMR (400 MHz, CDCl3) d=7.76 (d,
Preparation of compounds 44–49. To a suspension of
resin (22, 23, or 29: 200 mg, 0.150 mmol, 1.0 equiv) in
CH2Cl2 (2 mL) at 0 ꢁC was added triethylamine (0.558
mL, 4.00 mmol, 26.7 equiv) followed by COCl2 (20 wt%
by weight in toluene, 1.98 mL, 4.00 mmol, 26.7 equiv).
The resulting mixture was stirred at 0 ꢁC for 1 h and
then poured into a fritted funnel where the resin was
washed with CH2Cl2 (3Â10 mL) and Et2O (3Â10 mL).
After drying for 5 min, this resin was resuspended in
CH2Cl2 (3 mL) and appropriate R2NHx amine (benzyl-
amine or morpholine, 1.50 mmol, 10.0 equiv) and tri-
ethylamine (0.558 mL, 4.00 mmol, 26.7 equiv) were
added. The reaction mixture was stirred at 25 ꢁC for 18
h and then poured into a fritted funnel where the resin
was washed CH2Cl2 (4Â10 mL), MeOH (4Â10 mL),
and Et2O (4Â10 mL) and dried. The resin was then
suspended in toluene (2 mL), and n-Bu3SnH (0.162 mL,
0.600 mmol, 4.0 equiv) and AIBN (33 mg, 0.200 mmol,
1.3 equiv) were added, and the reaction mixture was
heated to 90 ꢁC and stirred for 2 h. After cooling to
25 ꢁC, the resin was removed by filtration, washed with
CH2Cl2 (4Â15 mL) and the resulting filtrate was con-
centrated to afford the crude products which were pur-
ified by column chromatography (5!50% EtOAc in
hexanes) to afford pure 44–49.
J=7.3 Hz, 2H), 6.64 (d, J=10.6 Hz, 1H), 5.98–5.88 (m,
1H), 5.17–5.08 (m, 2H), 4.02 (s, 2H), 3.85 (d, J=2.0
Hz, 3H), 3.31 (d, J=5.9 Hz, 2H); 13C NMR
(100 MHz, CDCl3) d=167.3, 149.3, 135.1, 132.1,
129.8, 122.7, 119.9, 116.7, 114.7, 51.6, 36.3; HRMS
calcd for C11H13NO2 [M+H+] 192.1019, found
192.1028.
20: Rf=0.12 (silica gel, EtOAc/hexanes 1:3); FT-IR
(neat) nmax 3486, 3382, 3248, 2979, 2712, 1635, 1488,
1435, 1310 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d=7.99–7.97 (m, 2H), 6.63 (d, J=9.4 Hz, 1H), 5.98–
5.88 (m, 1H), 5.23–5.13 (m, 2H), 4.43 (s, 2H), 3.32 (d,
J=6.2 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d=151.2, 139.0, 134.0, 126.5, 124.5, 122.7, 117.7, 114.0,
36.0; ESMS calcd for C9H10N2O2 [M+Na+] 201,
found 201.
21: Rf=0.22 (silica gel, EtOAc/hexanes 1:3); FT-IR
(neat) nmax 3433, 3359, 2942, 1608, 1503, 1432 cmꢀ1; 1H
NMR (400 MHz, CDCl3) d=6.67–6.62 (m, 3H), 5.99–
5.90 (m, 1H), 5.14–5.07 (m, 2H), 3.75 (s, 3H), 3.43 (s,
2H), 3.29 (d, J=6.2 Hz, 2H); 13C NMR (100 MHz,
CDCl3) d=153.1, 138.5, 135.8, 125.9, 117.1, 116.4,
116.1, 112.8, 55.8, 36.8; HRMS calcd for C10H13NO
[M+H+] 163.0997, found 163.0998.
Preparation of compounds 50–52. To a suspension of
resin (22, 23, or 29: 200 mg, 0.150 mmol, 1.0 equiv) in
CH2Cl2 (2 mL) at 0 ꢁC was added triethylamine (0.558
mL, 4.00 mmol, 26.7 equiv) followed by COCl2 (20 wt%
in toluene, 1.98 mL, 4.00 mmol, 26.7 equiv). The
resulting mixture was stirred at 0 ꢁC for 1 h and then
poured into a fritted funnel where the resin was washed
with CH2Cl2 (3Â10 mL) and Et2O (3Â10 mL). After
drying for 5 min, the resin was resuspended in CH2Cl2
(3 mL), and piperazine (128 mg, 1.5 mmol, 10.0 equiv)
and triethylamine (0.558 mL, 4.00 mmol, 26.7 equiv)
were added. The mixture was stirred at 25 ꢁC for 18 h
and then poured into a fritted funnel where the resin
was washed with CH2Cl2 (4Â10 mL), MeOH (4Â10
mL), and Et2O (4Â10 mL) and dried. This resin was
then resuspended in CH2Cl2 (5 mL) and DCC (310 mg,
1.5 mmol, 10.0 equiv), 4-DMAP (24 mg, 0.200 mmol,
1.3 equiv), and the corresponding carboxylic acid
Solid phase loading and cleavage of anilines 11–21
Representative procedure. Preparation of o-allyl aniline
11. To a suspension ofselenium bromide resin (200 mg
of0.75 mmol/g, 0.150 mmol, 1.0 equiv) in CH Cl2 (4
2
mL) at ꢀ20 ꢁC was added a solution of o-allyl aniline
(11) (80 mg, 0.60 mmol, 4.0 equiv) in CH2Cl2 (1 mL)
followed by addition of SnCl4 (0.825 mL ofa 1.0 M
solution in CH2Cl2, 0.825 mmol, 5.5 equiv). The reac-
tion mixture was slowly stirred at ꢀ20 ꢁC for 30 min
and then quenched by addition ofEt N (0.5 mL). The
3
resulting suspension was poured into a fritted funnel
and the resin was washed with CH2Cl2 (4Â15 mL),
MeOH (4Â15 mL), and Et2O (2Â15 mL). The resulting
resin was then suspended in toluene (2 mL), and
n-Bu3SnH (87.3 mg, 0.30 mmol, 2.0 equiv) and AIBN

472
K. C. Nicolaou et al. / Bioorg. Med. Chem. 11 (2003) 465–476
1
(41–43: 1.5 mmol, 10 equiv) were added. The resulting
mixture was stirred at 25 ꢁC for 48 h and then poured
into a fritted funnel where the resin was washed CH2Cl2
(4Â10 mL), MeOH (4Â10 mL), and Et2O (4Â10 mL)
and dried. The resulting resin was then suspended in
toluene (2 mL) and n-Bu3SnH (0.162 mL, 0.600 mmol,
4.0 equiv) and AIBN (33 mg, 0.200 mmol, 1.3 equiv)
were added, and the reaction mixture was heated to
90 ꢁC for 2 h after which time the resin was removed by
filtration and washed with CH2Cl2 (2Â10 mL). The fil-
trate was then concentrated and the crude reaction
products were purified by column chromatography
(5!100% EtOAc in hexanes) to afford pure 50–52.
51: H NMR (400 MHz, CDCl3) d=7.89–7.84 (m, 3H),
7.58–7.42 (m, 4H), 6.96–6.81 (m, 3H), 4.50–4.45 (m,
1H), 3.56–3.51 (m, 4H), 3.30–3.22 (m, 4H), 3.16 (dd,
J=15.8, 8.5 Hz, 1H), 2.58 (dd, J=15.0, 7.0 Hz, 1H),
2.26 (s, 3H), 1.36 (d, J=6.2 Hz, 3H); HRMS calcd for
C26H27N3O2 [M+Na+] 436.2001, found 436.2017.
1
52: H NMR (400 MHz, CDCl3) d=7.45–7.39 (m, 7H),
6.88 (d, J=8.5 Hz, 1H), 4.63–4.54 (m, 1H), 3.94–3.49
(m, 8H), 3.26 (dd, J=15.8, 8.8 Hz, 1H), 2.70 (dd,
J=16.2, 7.9 Hz, 1H), 1.40 (d, J=6.2 Hz, 3H); HRMS
calcd for C22H22N4O2 [M+Na+] 397.1640, found
397.1643.
1
44: H NMR (400 MHz, CDCl3) d=7.15–7.10 (m, 2H),
General procedure for construction and radical release of
polycyclic indolines 60–64
6.93–6.85 (m, 2H), 4.56–4.47 (m, 1H), 3.79–3.69 (m,
4H), 3.49–3.44 (m, 2H), 3.39–3.33 (m, 2H), 3.20 (dd,
J=15.5, 8.8 Hz, 1H), 2.64 (dd, J=15.5, 7.3 Hz, 1H),
1.39 (d, J=6.2 Hz, 3H); HRMS calcd for C14H18N2O2
[M+H+] 247.1446, found 247.1443.
Preparation of compounds 60–62. To a suspension of
resin 22 (200 mg, 0.150 mmol, 1.0 equiv) in CH2Cl2 (5
mL) at ambient temperature was added DCC (310 mg,
1.5 mmol, 10.0 equiv), 4-DMAP (24 mg, 0.200 mmol,
1.3 equiv), and carboxylic acid 55, 56 or 57 (1.5 mmol,
10.0 equiv). The resulting mixture was allowed to stir at
ambient temperature for 48 h and then poured into a
fritted funnel where the resin was washed with CH2Cl2
(5Â10 mL), MeOH (10Â10 mL), and Et2O (5Â10 mL).
This resin was then suspended in toluene (4 mL) and
warmed to 90 ꢁC. To the reaction mixture was added a
solution of n-Bu3SnH (0.162 mL, 0.600 mmol, 4.0
equiv) and AIBN (33 mg, 0.200 mmol, 1.3 equiv) in
toluene (1 mL) via syringe pump over a period of4 h.
After addition was completed, the reaction mixture was
cooled to 25 ꢁC and the resin was removed by filtration
and washed with CH2Cl2 (2Â10 mL). The filtrate was
then concentrated and the crude cyclization product
was purified by column chromatography (0!25%
EtOAc in hexanes) to afford pure 60–62. In all three
cases, only one diastereometric product was isolated.
1
45: H NMR (500 MHz, CDCl3) d=6.97 (s, 1H), 6.92
(d, J=8.0 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 4.53–4.45
(m, 1H), 3.78–3.69 (m, 4H), 3.45–3.41 (m, 2H), 3.36–
3.32 (m, 2H), 3.16 (dd, J=15.4, 8.4 Hz, 1H), 2.60 (dd,
J=15.8, 7.4 Hz, 1H), 2.27 (s, 3H), 1.37 (d, J=5.9 Hz,
3H); HRMS calcd for C15H20N2O2 [M+H+] 261.1603,
found 261.1615.
1
46: H NMR (500 MHz, CDCl3) d=7.42 (d, J=8.6 Hz,
1H), 7.37 (s, 1H), 6.87 (d, J=8.2 Hz, 1H), 4.61–4.53 (m,
1H), 3.78–3.67 (m, 4H), 3.55–3.49 (m, 2H), 3.38–3.32
(m, 2H), 3.24 (dd, J=15.8, 8.8 Hz, 1H), 2.68 (dd,
J=15.8, 7.9 Hz, 1H), 1.39 (d, J=6.2 Hz, 3H); ESMS
calcd for C15H17N3O2 [M+H+] 272, found 272.
1
47: H NMR (400 MHz, CDCl3) d=7.69 (d, J=8.5 Hz,
1H), 7.38–7.26 (m, 5H), 7.17 (t, J=7.0 Hz, 2H), 6.93 (t,
J=7.6 Hz, 1H), 5.05 (s, 1H), 4.60–4.50 (m, 2H), 4.45–
4.38 (m, 1H), 3.39 (dd, J=15.8, 9.1 Hz, 1H), 2.62 (d,
J=15.8 Hz, 1H), 1.31 (d, J=6.5 Hz, 3H); HRMS calcd
for C17H18N2O [M+Na+] 289.1317, found 289.1321.
Preparation of compounds 63 and 64. To a suspension of
resin 22 (200 mg, 0.150 mmol, 1.0 equiv) in DMF (4
mL) was added alkenyl bromide 58 or 59 (1.5 mmol,
10.0 equiv) and NaH (60% dispersion in mineral oil,
120 mg, 3.0 mmol, 20.0 equiv). The reaction mixture
was heated to 40 ꢁC for 48 h and then cooled to 25 ꢁC
and quenched with methanol (5 mL). The resulting sus-
pension was poured into a fritted funnel where the resin
was washed with CH2Cl2 (4Â10 mL), MeOH (4Â10 mL),
and Et2O (4Â10 mL). After drying the resin was cleaved
as described above to provide polycycles 63 and 64.
1
48: H NMR (500 MHz, CDCl3) d=7.53 (d, J=8.0 Hz,
1H), 7.37–7.26 (m, 6H), 6.97 (d, J=9.5 Hz, 1H), 5.02 (s,
1H), 4.58–4.49 (m, 2H), 4.46–4.37 (m, 1H), 3.35 (dd,
J=15.8, 9.2 Hz, 1H), 2.57 (d, J=15.8 Hz, 1H), 2.28 (s,
3H), 1.30 (d, J=6.6 Hz, 3H); HRMS calcd for
C18H20N2O [M+H+] 281.1654, found 281.1645.
1
49: H NMR (400 MHz, CDCl3) d=7.97 (d, J=8.5 Hz,
1
1H), 7.54–7.47 (m, 1H), 7.39–7.29 (m, 6H), 5.03 (s, 1H),
4.54 (d, J=5.6 Hz, 2H), 4.41–4.35 (m, 1H), 3.41 (dd,
J=16.1, 9.4 Hz, 1H), 2.70 (d, J=16.1 Hz, 1H), 1.33 (d,
J=6.2 Hz, 3H); HRMS calcd for C18H17N3O [M+H+]
292.1450, found 292.1446.
60: H NMR (500 MHz, CDCl3) d=7.59 (d, J=8.1 Hz,
1H), 7.26–7.17 (m, 2H), 7.01 (t, J=7.4 Hz, 1H), 4.59–
4.53 (m, 1H), 3.17 (dd, J=15.4, 8.5 Hz, 1H), 2.85 (dd,
J=15.1, 9.9 Hz, 1H), 2.38 (dd, J=12.1, 5.9 Hz, 1H),
2.31–2.26 (m, 1H), 1.91–1.84 (m, 4H), 1.70–1.66 (m, 2H),
1.50–1.45 (m, 1H), 1.36–1.21 (m, 1H); HRMS calcd for
C15H17NO [M+H+] 228.1388, found 228.1380.
1
50: H NMR (500 MHz, CDCl3) d=7.41–7.35 (m, 4H),
7.16–7.10 (m, 2H), 6.91–6.87 (m, 2H), 4.55–4.48 (m,
1H), 3.86–3.36 (m, 8H), 3.22 (dd, J=15.8, 8.8 Hz, 1H),
2.65 (dd, J=15.8, 7.4 Hz, 1H), 1.39 (d, J=6.3 Hz, 3H);
HRMS calcd for C21H22ClN3O2 [M+Na+] 406.1298,
found 406.1314.
1
61: H NMR (400 MHz, CDCl3) d=7.23–7.17 (m, 3H),
7.04–7.00 (m, 1H), 4.60–4.52 (m, 1H), 3.18 (dd, J=15.5,
8.5 Hz, 1H), 2.84 (dd, J=15.3, 10.0 Hz, 1H), 2.61 (dd,
J=12.3, 5.9 Hz, 1H), 1.95–1.88 (m, 1H), 1.80–1.58 (m,

K. C. Nicolaou et al. / Bioorg. Med. Chem. 11 (2003) 465–476
473
6H), 1.47–1.10 (m, 4H); HRMS calcd for C16H19NO
[M+H+] 242.1545, found 242.1541.
2.34 (s, 3H); HRMS calcd for C16H15NO2S [M+H+]
286.0896, found 286.0901.
1
1
62: H NMR (400 MHz, CDCl3) d=7.67 (d, J=7.7 Hz,
71: H NMR (400 MHz, CDCl3) d=8.15 (d, J=7.9 Hz,
1H), 7.41–7.01 (m, 8H), 4.51–4.43 (m, 1H), 3.40 (dd,
J=14.1, 4.4 Hz, 1H), 3.18–3.10 (m, 2H), 2.83 (dd,
J=15.5, 9.7 Hz, 1H), 2.63 (dd, J=14.1, 10.3 Hz, 1H),
2.50–2.41 (m, 1H), 1.50–1.43 (m, 1H); HRMS calcd for
C18H17NO [M+H+] 264.1388, found 264.1386.
1H), 7.77 (d, J=7.9 Hz, 2H), 7.52 (t, J=7.9 Hz, 1H),
7.44–7.40 (m, 3H), 7.22–7.20 (m, 2H), 6.35 (s, 1H), 2.60
(s, 3H); HRMS calcd for C15H13NO2S [M+H]
271.06615, found 271.066. 72: 1H NMR (400 MHz,
CDCl3) d=7.72 (d, J=8.2 Hz, 2H), 7.63 (t, J=6.7 Hz,
1H), 7.51–7.46 (m, 3H), 7.14–7.12 (m, 1H), 7.01–7.00
(m, 2H), 6.43 (s, 1H), 2.41 (s, 3H); HRMS calcd for
C16H13NO [M+H+] 236.1070, found 236.1064.
1
63: H NMR (250 MHz, CDCl3) d=7.12–7.05 (m, 2H),
6.75 (td, J=7.3, 1.1 Hz, 1H), 6.57 (d, J=7.7 Hz, 1H),
4.17–4.03 (m, 1H), 3.43 (dd, J=11.3, 6.9 Hz, 1H), 3.21
(dd, J=16.1, 9.5 Hz), 2.98–2.85 (m, 2H), 2.19 (oct,
J=6.6 Hz, 1H), 1.60 (dd, J=7.3, 6.6 Hz, 2H), 1.06 (d,
J=7.0 Hz, 3H); HRMS calcd for C12H15N [M+H+]
174.1277, found 174.1281.
1
73: H NMR (500 MHz, CDCl3) d=7.71 (d, J=7.0 Hz,
2H), 7.47 (d, J=7.7 Hz, 1H), 7.14–7.10 (m, 1H), 7.02–
6.95 (m, 4H), 6.42 (s, 1H), 3.90 (s, 3H), 2.44 (d, J=1.1
Hz, 3H); HRMS calcd for C17H15NO2 [M+ꢂ] 264.1019,
found 264.1010.
1
64: H NMR (400 MHz, CDCl3) d=7.16–7.08 (m, 2H),
1
6.87–6.75 (m, 2H), 4.25–4.16 (m, 1H), 3.74 (dd, J=10.3,
7.9 Hz, 1H), 3.45 (dd, J=11.4, 7.0 Hz, 1H), 3.26 (dd,
J=16.1, 9.1 Hz, 1H), 3.07 (dd, J=11.4, 7.3 Hz, 1H),
2.90 (dd, J=16.4, 3.8 Hz, 1H), 2.02 (m, 1H), 1.71 (m,
1H), 1.43 (quint, J=7.3 Hz, 2H), 0.91 (t, J=7.3 Hz,
3H); HRMS calcd for C13H17N [M+H+] 188.1434,
found 188.1439.
74: H NMR (400 MHz, CDCl3) d=7.64 (d, J=7.9 Hz,
1H), 7.49 (d, J=7.6 Hz, 1H), 7.20–7.13 (m, 2H), 6.33–
6.30 (m, 1H), 6.03–5.98 (m, 1H), 5.72 (m, 1H), 5.31–5.26
(m, 2H), 2.59 (s, 3H); HRMS calcd for C13H14N2O
[M+H+] 215.1179, found 215.1189.
1
75: H NMR (500 MHz, CDCl3) d=7.60 (dd, J=1.4,
6.9 Hz, 1H), 7.48–7.47 (m, 1H), 7.40–7.38 (m, 4H),
7.35–7.34 (m, 1H), 7.15–7.11 (m, 2H), 6.32–6.30 (m,
1H), 5.94 (bs, 1H), 4.69 (d, J=5.8 Hz, 2H), 2.59 (d,
J=1.1 Hz, 3H); HRMS calcd for C17H16N2O
[M+Na+] 287.1155, found 287.1150.
Procedure for solid phase synthesis of 2-methyl indoles
70–75
Acylation procedure A. To a suspension ofresin 22 (200
mg, 0.150 mmol, 1.0 equiv) in CH2Cl2 (5 mL) at 25 ꢁC
was added diisopropylethylamine (0.52 mL, 3.0 mmol,
20 equiv), 4-DMAP (18 mg, 0.15 mmol, 1.0 equiv), and
the appropriate electrophile (1.5 mmol, 10 equiv). The
resulting mixture was stirred for 48 h and then poured into
a fritted funnel and the resin was washed with CH2Cl2
(4Â15 mL), MeOH (4Â15 mL), and Et2O (2Â15 mL)
Analytical data for o-prenylated carbamates 78, 81–84
78: Rf=0.25 (silica gel, EtOAc:hexanes 1:3); FT-IR
(neat) nmax 2226, 1740, 1584, 1522, 1298, 1215, 1058
1
cmꢀ1; H NMR (400 MHz, CDCl3) d=8.10 (d, J=8.5
Hz, 1H), 7.50 (dd, J=8.5, 1.7 Hz, 1H), 7.41 (s, 1H), 6.92
(s, 1H), 5.15 (t, J=7.0 Hz, 1H), 4.22 (q, J=7.0 Hz, 2H),
3.28 (d, J=7.0 Hz, 2H), 1.79 (s, 6H), 1.31 (t, J=7.4 Hz,
3H); 13C NMR (100 MHz, CDCl3) d=153.0, 140.7,
136.1, 133.0, 131.4, 129.6, 119.7, 119.6 119.1, 106.0,
61.6, 30.9, 25.6, 17.7, 14.4; HRMS calcd for
C15H18N2O2 [M+Na+] 281.1260, found 281.1270.
Acylation procedure B. To a suspension ofresin 33 (200
mg, 0.150 mmol, 1.0 equiv) in CH2Cl2 (5 mL) at 0 ꢁC
was added triethylamine (0.42 mL, 3.0 mmol, 20 equiv)
and COCl2 (1.5 mL ofa 20% solution by weight in tol-
uene). The reaction mixture was stirred for 1 h and then
poured into a fritted funnel and the resin was washed
with CH2Cl2 (4Â15 mL) and Et2O (2Â15 mL). The
resin was then resuspended in CH2Cl2 (5 mL) at 25 ꢁC,
and triethylamine (0.42 mL, 3.0 mmol, 20 equiv) and
the appropriate amine (3.0 mmol, 20 equiv) were added.
The reaction mixture was stirred for 18 h and then
poured into a fritted funnel, and the resin was washed
with CH2Cl2 (4Â15 mL), MeOH (4Â15 mL), and Et2O
(2Â15 mL). The resin was then resuspended in benzene
(10 mL) at 25 ꢁC and treated with AIBN (74 mg, 0.45
mmol, 3.0 equiv). The reaction mixture was then heated
at 85ꢁC and stirred for 48 h. The reaction mixture was
then filtered and the filtrate was directly concentrated and
purified by PTLC (30% ethyl acetate/hexane) and ana-
lyzed by HRMS and 1H NMR spectroscopic methods.
81: Rf=0.74 (silica gel, EtOAc/hexanes 1:3); FT-IR
(neat) nmax 1690, 1527, 1451, 1252, 1236, 1094 cmꢀ1; 1H
NMR (400 MHz, CDCl3) d=7.53 (s, 1H), 6.86 (s, 1H),
6.60 (s, 1H) 5.09–5.07 (m, 1H), 4.29 (q, J=5.9 Hz, 2H),
3.36 (d, J=5.3 Hz, 2H), 2.36 (s, 6H), 1.91 (s, 3H), 1.81 (s,
3H), 1.38 (t, J=5.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d=154.7, 136.7, 136.5, 136.4, 133.6, 127.6, 122.0, 121.0,
116.7 61.4, 27.2, 26.1, 21.5, 20.6, 18.2, 15.0; HRMS calcd
for C16H23NO2 [M+H+] 262.1801, found 262.1805.
82: Rf=0.60 (silica gel, EtOAc:hexanes 1:3); FT-IR
(neat) nmax 1688, 1527, 1477, 1398, 1245, 1062 cmꢀ1; 1H
NMR (400 MHz, CDCl3) d=7.71 (bs, 1H), 7.32 (dd,
J=8.4, 2.2 Hz, 1H), 7.26 (d, J=2.2 Hz, 1H), 6.62 (bs,
1H), 5.17–5.14 (m, 1H), 4.21 (q, J=7.3 Hz, 2H), 3.24 (d,
J=6.9 Hz, 2H), 1.78 (s, 6H), 1.30 (t, J=7.3 Hz, 3H);
13C NMR (100 MHz, CDCl3) d=153.6, 135.3, 134.9,
134.8, 132.1, 129.9, 129.8, 120.6, 116.5, 61.2, 31.0, 25.6,
1
70: H NMR (400 MHz, CDCl3) d=8.14 (d, J=8.2 Hz,
1H), 7.65 (d, J=8.2 Hz, 2H), 7.39 (d, J=7.9 Hz, 1H),
7.21–7.17 (m, 4H), 6.73 (s, 1H), 2.59 (d, J=1.1 Hz, 3H),

474
K. C. Nicolaou et al. / Bioorg. Med. Chem. 11 (2003) 465–476
17.7, 14.5; HRMS calcd for C14H18NBrO2 [M+Na+]
334.0415, found 334.0415.
(0.450 mL ofa 1.0 M solution in CH Cl2, 0.450 mmol,
2
3.0 equiv). The reaction mixture was slowly stirred at
0 ꢁC for 2 h and then quenched by addition of Et3N (2.0
mL). The resulting suspension was poured into a fritted
funnel and the resin was washed with CH2Cl2 (4Â15
mL), MeOH (4Â15 mL), and Et2O (2Â15 mL). The
resulting resin was then resuspended in THF (5 mL) at
25 ꢁC and treated with H2O2 (0.10 mL ofa 30 wt.%
aqueous solution, 0.90 mmol, 60 equiv). The reaction
mixture was then slowly stirred for 1 h, and the resulting
suspension was then filtered. The excess H2O2 was
83: Rf=0.22 (silica gel, EtOAc/hexanes 1:3); FT-IR
(neat) nmax 1736, 1718, 1589, 1524, 1278, 1207, 1101
1
cmꢀ1; H NMR (400 MHz, CDCl3) d=8.00 (d, J=8.5
Hz, 1H), 7.88 (dd, J=8.5, 4.0 Hz, 1H), 7.80 (d, J=2.1
Hz, 1H), 6.93 (s, 1H), 4.19 (q, J=7.0 Hz, 2H), 3.85 (s,
3H), 3.30 (d, J=7.0 Hz, 2H), 1.78 (s, 3H), 1.75 (s, 3H),
1.28 (t, J=7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d=166.6, 153.1, 140.7, 134.8, 130.9, 128.9, 128.8, 124.5,
120.7, 119.0, 61.2, 51.7, 31.2, 28.0, 17.6, 14.3; HRMS
calcd for C16H21NO4 [M+H+] 292.1543, found
292.1545.
quenched by the addition of1.0 M Na SO3 (5 mL). The
2
aqueous phase was then extracted with Et2O (3Â10 mL),
and the combined extracts were dried over MgSO4 and
concentrated. The crude product (35 mg, 90% yield) was
analyzed for purity by 1H NMR (>95% purity).
84: Rf=0.13 (silica gel, EtOAc:hexanes 1:3); FT-IR
(neat) nmax 1734, 1560, 1541, 1508, 1340, 1213 cmꢀ1; 1H
NMR (400 MHz, CDCl3) d=8.15 (d, J=9.1 Hz, 1H),
8.05 (dd, J=9.1, 2.6 Hz, 1H), 7.99 (d, J=2.6 Hz, 1H),
7.06 (s, 1H), 5.18–5.14 (m, 1H), 4.21 (q, J=7.3 Hz, 2H),
3.34 (d, J=7.0 Hz, 2H), 1.79–1.78 (m, 6H), 1.29 (t,
J=7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) d=152.8,
142.6, 142.5, 136.1, 129.2, 124.7, 122.9, 119.5, 118.7,
61.7, 31.0, 25.6, 17.7, 14.2; ESI calcd for C14H18N2O4
[M+Na+] 301, found 301.
1
80: H NMR (400 MHz, CDCl3) d=7.51 (d, J=8.5 Hz,
1H), 7.38 (s, 1H), 4.90 (dd, J=10.5, 2.9 Hz, 1H), 4.79 (s,
2H), 4.33–4.22 (m, 2H), 3.44 (dd, J=16.7, 10.9 Hz, 1H),
2.85 (dd, J=16.7, 3.2 Hz, 1H), 1.66 (s, 3H), 1.31 (t,
J=6.9 Hz, 3H); GCMS calcd for C15H16N2O2 [M+H]
256, found 256.
1
85: H NMR (400 MHz, CDCl3) d=6.70 (s, 1H), 4.94
(bd, J=7.6 Hz, 1H), 4.85 (d, J=29.4 Hz, 2H), 4.32 (bs,
1H), 3.38–3.32 (m, 1H), 2.76 (d, J=12.9 Hz, 1H), 2.39
(s, 3H), 2.24 (s, 3H), 1.75 (s, 3H), 1.38 (b, 3H); HRMS
calcd for C16H21NO2 [M+H+] 260.1645, found
260.1648.
Procedure for the loading of the 2,2-dimethyldihydro-
quinoline template 77
To a suspension ofselenium bromide resin (200 mg of
0.75 mmol/g, 0.150 mmol, 1.0 equiv) in CH2Cl2 (4 mL)
at 0 ꢁC was added a solution of4-cyano-2-prenylaniline
(75) (56 mg, 0.30 mmol, 2.0 equiv) in CH2Cl2 (1 mL).
The resulting mixture was slowly stirred at 0 ꢁC for 30
min, and the resulting suspension was poured into a
fritted funnel and the resin was washed with CH2Cl2
(4Â15 mL), MeOH (4Â15 mL), and Et2O (2Â15 mL).
The resulting resin was then resuspended in THF (5
mL) at 25 ꢁC and treated with H2O2 (0.10 mL ofa 30
wt.% aqueous solution, 0.90 mmol, 6 equiv). The reac-
tion mixture was then slowly stirred for 1 h, and the
resulting suspension was then filtered. The excess H2O2
1
86: H NMR (400 MHz, CDCl3) d=7.29 (d, J=9.1 Hz,
1H), 7.24 (s, 1H), 4.86 (d, J=9.4 Hz, 1H), 4.79 (d,
J=14.7 Hz, 2H), 4.26–4.25 (m, 2H), 3.42 (dd, J=16.4,
10.6 Hz, 1H), 2.80 (dd, J=16.7, 2.6 Hz, 1H), 1.66 (s,
3H), 1.35–1.29 (b, 3H); HRMS calcd for C14H16BrNO2
[M+H+] 310.0437, found 310.0443.
1
87: H NMR (400 MHz, CDCl3) d=7.92 (d, J=7.3 Hz,
1H), 7.80 (s, 1H), 4.90 (dd, J=12.8, 2.6 Hz, 1H), 4.79
(d, J=14.4 Hz, 2H), 4.28–4.21 (m, 2H), 3.87 (s, 3H),
3.45 (dd, J=16.7, 10.8 Hz, 1H), 2.85 (dd, J=13.5, 2.9
Hz, 1H), 1.65 (s, 3H), 1.34 (t, J=14.6 Hz, 3H); HRMS
calcd for C16H19NO4 [M+H+] 290.1387, found
290.1386.
was quenched by the addition of1.0 M Na SO3 (5 mL).
2
The aqueous phase was then extracted with Et2O (3Â10
mL), and the combined extracts were dried over MgSO4
and concentrated. The crude product (24 mg, 85%
yield) was analyzed for purity by 1H NMR (>95%
purity).
1
88: H NMR (400 MHz, CDCl3) d=8.15 (d, J=6.8 Hz,
1H), 8.01 (s, 1H), 4.96 (dd, J=10.3, 2.6 Hz, 1H), 4.81 (s,
2H), 4.31–4.28 (m, 2H), 3.49 (dd, J=16.1, 10.0 Hz, 1H),
2.91 (dd, J=16.7, 2.6 Hz, 1H), 1.68 (s, 3H), 1.33 (t,
J=7.0 Hz, 3H); HRMS calcd for C14H16N2O4
[M+H+] 277.1183, found 277.1178.
1
77: H NMR (400 MHz, CDCl3) d=7.18 (dd, J=8.1,
1.8 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H), 6.33 (d, J=8.1 Hz,
1H), 6.19 (d, J=9.9 Hz, 1H), 5.50 (d, J=9.6 Hz, 1H),
4.11 (bs, 1H) 1.34 (s, 6H); HRMS calcd for C12H12N2
[M+H+] 185.1073, found 185.1067.
Representative procedure for solid phase synthesis of
2-propenyl indolines 91–102
General procedure for the loading of the 2-propenyl
indoline templates 80, 85–88
To a suspension ofresin 79 (200 mg, 0.150 mmol, 1.0
equiv) in toluene (5 mL) at 25 ꢁC was added azidoti-
methyltin (308 mg, 1.50 mmol, 10 equiv) as a solid. The
reaction mixture was then heated to 100 ꢁC and stirred
for 12 h, and the resulting suspension was poured into a
fritted funnel and the resin was washed with CH2Cl2
(4Â15 mL), MeOH (4Â15 mL), and Et2O (2Â15 mL).
To a suspension ofselenium bromide resin (200 mg of
0.75 mmol/g, 0.150 mmol, 1.0 equiv) in CH2Cl2 (4 mL)
at 0 ꢁC was added a solution ofthe ethyl carbamate of
4-cyano-2-prenylaniline (78, 77 mg, 0.30 mmol, 2.0
equiv) in CH2Cl2 (1 mL) followed by addition of SnCl4

K. C. Nicolaou et al. / Bioorg. Med. Chem. 11 (2003) 465–476
475
After drying for 30 min, the resulting resin was resus-
pended in CH2Cl2:TFA (20:1, 10 mL) at 25 ꢁC and stir-
red for 1 h. The reaction mixture was poured into a
fritted funnel and the resin was washed with CH2Cl2
(4Â15 mL), MeOH (4Â15 mL), and Et2O (2Â15 mL).
The resin was then resuspended in CH3CN (5 mL), and
appropriate alkylating agent (R1X, 3.0 mmol, 20.0
equiv) and diisopropylethylamine (0.78 mL, 4.5 mmol,
30 equiv) were added. The reaction mixture was heated
to 80 ꢁC for 12 h, cooled to 25 ꢁC, and then poured into
a fritted funnel and the resin was washed with CH2Cl2
(4Â15 mL), MeOH (4Â15 mL), and Et2O (2Â15 mL).
For compounds 100–102, the resulting resin was resus-
pended in THF (4 mL) at 25 ꢁC and treated with H2O2
(0.10 mL ofa 30 wt.% aqueous solution, 0.90 mmol, 6.0
equiv), and slowly stirred for 1 h, and the resulting sus-
pension was then filtered. The excess H2O2 was quen-
ched by the addition of1.0 M Na 2SO3 (5 mL). The
aqueous phase was then extracted with Et2O (3Â10
mL), and the combined extracts were dried over MgSO4
and concentrated. The compounds were purified by
PTLC (30% ethyl acetate/hexane) and analyzed by
HRMS and 1H NMR spectroscopic methods. For
compounds 91–99, the resulting resin was resuspended
in toluene (5 mL) and to this was added a pre-mixed
5.05 (s, 1H), 4.81 (dd, J=10.6, 4.4 Hz, 1H), 4.44 (s, 3H),
3.65 (dd, J=16.8, 10.6 Hz, 1H), 3.40–3.35 (m, 2H), 3.03
(dd, J=16.9, 4.4 Hz, 1H), 1.78 (s, 3H), 1.60–1.57 (m,
2H), 1.44–1.42 (m, 2H), 1.02 (t, J=7.4 Hz, 3H); HRMS
calcd for C18H24N6O [M+H+] 341.2084, found
341.2085.
1
95: H NMR (500 MHz, CDCl3) d=8.14 (d, J=8.4 Hz,
1H), 8.03 (d, J=8.4 Hz, 1H), 7.94 (s, 1H), 7.51–7.42 (m,
5H), 5.85 (s, 2H), 5.18 (s, 1H), 5.06 (t, J=5.1 Hz, 1H),
5.04 (s, 1H), 4.80 (dd, J=10.6, 4.1 Hz, 1H), 3.64 (dd,
J=16.5, 11.0 Hz, 1H), 3.38–3.33 (m, 2H), 3.01 (dd,
J=16.8, 4.4 Hz, 1H), 1.76 (s, 3H), 1.60–1.57 (m, 2H),
1.45–1.39 (m, 2H), 1.01 (t, J=7.4 Hz, 3H); HRMS
calcd for C24H28N6O [M+H+] 217.2397, found
417.2385.
1
96: H NMR (500 MHz, CDCl3) d=8.13 (d, J=8.4 Hz,
1H), 8.02 (d, J=8.4 Hz, 1H), 7.93 (s, 1H), 7.42 (d,
J=8.5 Hz, 2H), 6.97 (d, J=8.8 Hz, 2H), 5.78 (s, 2H),
5.17 (s, 1H), 5.06 (t, J=5.2 Hz, 1H), 5.04 (s, 1H), 4.79
(dd, J=10.6, 4.4 Hz, 1H), 3.89 (s, 3H), 3.63 (dd,
J=16.5, 10.6 Hz, 1H), 3.39–3.33 (m, 2H), 3.00 (dd,
J=16.9, 4.4 Hz, 1H), 1.75 (s, 3H), 1.61–1.56 (m, 2H);
HRMS calcd for C25H30N6O2 [M+H+] 447.2503,
found 447.2508.
2
solution ofamine (R NH2, 3.0 mmol, 20.0 equiv) and
trimethylaluminum (0.15 mL ofa 2.0 M solution in
toluene, 3.0 mmol, 20.0 equiv). The reaction mixture
was then heated to 90 ꢁC for 12 h, cooled to 25 ꢁC, and
then poured into a fritted funnel and the resin was
washed with CH2Cl2 (4Â15 mL), MeOH (4Â15 mL),
and Et2O (2Â15 mL). The compounds were then oxi-
datively cleaved from the solid support and subse-
quently purified in a manner analogous to that used for
compounds 30–32.
1
97: H NMR (500 MHz, CDCl3) d=8.18 (d, J=8.4 Hz,
1H), 8.04 (d, J=8.4 Hz, 1H), 7.96 (s, 1H), 7.43–7.37 (m,
5H), 5.43 (t, J=5.5 Hz, 1H), 5.13 (s, 1H), 5.00 (s, 1H),
4.85 (dd, J=11.0, 4.4 Hz, 1H), 4.58 (d, J=5.8 Hz, 2H),
4.45 (s, 3H), 3.67 (dd, J=16.8, 11.0 Hz, 1H), 3.04 (dd,
J=16.8, 4.8 Hz, 1H), 1.76 (s, 3H); HRMS calcd for
C21H22N6O [M+H+] 375.1928, found 375.1925.
1
98: H NMR (500 MHz, CDCl3) d=8.17 (d, J=8.4 Hz,
1
91: H NMR (500 MHz, CDCl3) d=8.16 (d, J=8.8 Hz,
1H), 8.03 (d, J=8.4 Hz, 1H), 7.95 (s, 1H), 7.49–7.38 (m,
10H), 5.85 (s, 2H), 5.40 (t, J=5.5 Hz, 1H), 5.12 (s, 1H),
4.99 (s, 1H), 4.84 (dd, J=10.6, 4.4 Hz, 1H), 4.57 (d,
J=5.2 Hz, 2H), 3.65 (dd, J=16.8, 11.0 Hz, 1H), 3.02
(dd, J=16.8, 4.4 Hz, 1H), 1.78 (s, 3H); HRMS calcd for
C28H28N6O2 [M+H+] 481.2346, found 481.2346.
1H), 8.03 (d, J=8.4 Hz, 1H), 7.96 (s, 1H), 6.01–5.96 (m,
1H), 5.29–5.22 (m, 3H), 5.15–5.13 (m, 1H), 5.06–5.04
(m, 1H), 4.84 (dd, J=10.6, 4.4 Hz, 1H), 4.48 (s, 3H),
4.06–3.99 (m, 2H), 3.68 (dd, J=16.9, 11.0 Hz, 1H), 3.04
(dd, J=16.5, 4.4 Hz, 1H), 1.77 (s, 3H); HRMS calcd for
C17H20N6O2 [M+H+] 325.1771, found 325.1774.
1
99: H NMR (500 MHz, CDCl3) d=8.16 (d, J=8.4 Hz,
1
92: H NMR (500MHz, CDCl3) d=8.14 (d, J=8.4 Hz,
1H), 8.03 (d, J=8.4 Hz, 1H), 7.95 (s, 1H), 7.45–7.38 (m,
6H), 6.97 (d, J=8.3 Hz, 2H), 5.78 (s, 2H), 5.40 (t,
J=5.1 Hz, 1H), 5.12 (s, 1H), 4.99 (s, 1H), 4.84 (dd,
J=10.6, 4.4 Hz, 1H), 4.58 (d, J=5.5 Hz, 2H), 3.87 (s,
3H), 3.65 (dd, J=16.6, 11.0 Hz, 1H), 3.01 (dd, J=16.8,
4.4 Hz, 1H), 1.74 (s, 3H); HRMS calcd for C27H26N6O
[M+H+] 451.2241, found 451.2235.
1H), 8.03 (d, J=8.4 Hz, 1H), 7.95 (s, 1H), 7.47–7.41 (m,
5H), 6.01–5.94 (m, 1H), 5.85 (s, 2H), 5.28–5.18 (m, 3H),
5.13–5.10 (m, 1H), 5.05–5.03 (m, 1H), 4.84 (dd, J=10.6,
4.0 Hz, 1H), 4.03–3.99 (m, 2H), 3.66 (dd, J=16.5, 10.6 Hz,
1H), 3.02 (dd, J=16.5, 4.0 Hz, 1H), 1.77 (s, 3H); HRMS
calcd for C23H24N6O [M+H+] 401.2084, found 401.2077.
1
1
93: H NMR (500 MHz, CDCl3) d=8.13 (d, J=8.5 Hz,
100: H NMR (400 MHz, CDCl3) d=7.98 (d, J=7.6
1H), 8.02 (d, J=8.8 Hz, 1H), 7.94 (s, 1H), 7.44 (d,
J=8.4 Hz, 2H), 6.97 (d, J=8.8 Hz, 2H), 6.01–5.95 (m,
1H), 5.78 (s, 2H), 5.28–5.19 (m, 3H), 5.14–5.12 (m, 1H),
4.83 (dd, J=11.0, 4.4 Hz, 1H), 4.06–3.95 (m, 2H), 3.87
(s, 3H), 3.65 (dd, J=16.9, 11.0 Hz, 1H), 3.01 (dd,
J=16.5, 4.0 Hz, 1H), 1.78 (s, 3H); HRMS calcd for
C24H26N6O2 [M+H+] 431.2190, found 431.2181.
Hz, 1H), 7.90 (s, 1H), 4.91 (d, J=8.8 Hz, 1H), 4.83 (s,
1H), 4.78 (s, 1H), 4.37 (s, 3H), 4.29–4.27 (m, 2H), 3.50
(dd, J=16.4, 11.1 Hz, 1H), 2.89 (dd, J=16.4, 3.2 Hz,
1H), 1.68 (s, 3H), 1.36–1.30 (m, 3H); HRMS calcd for
C16H19N5O2 [M+H+] 314.1611, found 314.1621.
1
101: H NMR (400 MHz, CDCl3) d=7.98 (d, J=8.5
Hz, 1H), 7.89 (s, 1H), 7.41–7.37 (m, 5H), 5.78 (s, 2H),
4.90 (d, J=10.3 Hz, 1H), 4.82 (s, 1H), 4.76 (s, 1H),
4.28–4.26 (m, 2H), 3.47 (dd, J=16.1, 10.8 Hz, 1H), 2.87
1
94: H NMR (500 MHz, CDCl3) d=8.16 (d, J=8.5 Hz,
1H), 8.02 (d, J=8.7 Hz, 1H), 7.95 (s, 1H), 5.19 (s, 1H),

476
K. C. Nicolaou et al. / Bioorg. Med. Chem. 11 (2003) 465–476
(dd, J=16.4, 2.8 Hz, 1H), 1.66 (s, 3H), 1.33–1.30 (m,
3H); HRMS calcd for C22H23N5O2 [M+H+] 390.1924,
found 390.1907.
R. G.; Abood, M. E. J. Med. Chem. 1998, 41, 5177. For the
anticancer agent see: (c) Yoon, S. J.; Chung, Y.; Lee, M. S.;
Choi, D. R.; Lee, J. A.; Yun, D. K.; Moon, E. Y.; Hwang, H.
S.; Choi, C. H.; Jung, S. H. Patent WO 9807719 (Dong Wha
Pharm. Ind. Co., Ltd., S. Korea) [Chem. Abs. 128:204885].
6. For the synthesis ofpolymer-bound phenylselenenyl bro-
mide resin see: Nicolaou, K. C.; Pastor, J.; Barluenga, S.;
Winssinger, N. Chem. Commun. 1998, 1947.
1
102: H NMR (400 MHz, CDCl3) d=7.97 (d, J=8.2
Hz, 1H), 7.88 (s, 1H), 7.36 (d, J=8.8 Hz, 2H), 6.89 (d,
J=8.8 Hz, 2H), 5.70 (s, 2H), 4.90 (d, J=8.8 Hz, 1H),
4.82 (s, 1H), 4.76 (s, 1H), 4.28–4.26 (m, 2H), 3.79 (s,
3H), 3.47 (dd, J=16.7, 10.8 Hz, 1H), 2.87 (dd, J=16.4,
2.6 Hz, 1H), 1.66 (s, 3H), 1.33–1.31 (m, 3H); HRMS
calcd for C23H25N5O3 [M+Na+] 442.1849, found
442.1850.
7. (a) Bermudez, J.; Dabbs, S.; Joiner, K. A.; King, F. D. J.
Med. Chem. 1990, 33, 1929. (b) Adachi, S.; Koike, K.;
Takayanagi, I. Pharmacology 1996, 53, 250.
8. To the best ofour knowledge, this is the first example
whereby radical cleavage from a solid support is accompanied
by an intramolecular cyclization to afford an additional ring
system in the target molecule. Solid phase non-releasing radical
cyclizations have been described previously, for representative
examples, see: (a) Du, X.; Armstrong, R. W. J. Org. Chem.
1997, 62, 5678. (b) Watanabe, Y.; Ishikawa, S.; Takao, G.;
Toru, T. Tetrahedron Lett. 1999, 40, 3411. (c) Miyabe, H.;
Tanaka, H.; Naito, T. Tetrahedron Lett. 1999, 40, 8387.
9. For solution phase radical-based syntheses ofsubstituted
indoles see: (a) Reding, M. T.; Kaburagi, Y.; Tokuyama, H.;
Fukuyama, T. Heterocycles 2002, 56, 313. (b) Ziegler, F. E.;
Harran, P. G. J. Org. Chem. 1993, 58, 2768. For a recent solid
phase synthesis ofsubstituted indoles see: (c) Wu, T. Y. H.;
Ding, S.; Gray, N. S.; Schultz, P. G. Org. Lett. 2001, 3, 3827.
10. For solution phase precedent, see: (a) Clive, D. L. J.;
Wong, C. K.; Kiel, W. A.; Menchen, S. M. J. Chem. Soc.
Chem. Commun. 1978, 379. (b) Clive, D. L. J.; Farina, V.;
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Acknowledgements
Financial support for this work was provided by the
Skaggs Institute for Chemical Biology, The National
Institutes of Health (USA), fellowships from the Divi-
sion ofOrganic Chemistry ofthe American Chemical
Society (to A.R.), the Division ofMedicinal Chemistry
ofthe American Chemical Society (to R.H.), Dr. Saal
van Zwanenbergstichting (to R.v.S.), and the Depart-
ment of Defense (to J.P.), and grants from American
BioScience, Amgen, Array Biopharma, Boehringer-
Ingelheim, Glaxo, Hoffmann-LaRoche, DuPont,
Merck, Novartis, Pfizer, and Schering Plough.
11. Separation ofthe desired indoline cleavage products from
organotin by-products represents an obstacle to the combina-
torial use ofthis methodology, and as such, new strategies are
needed to overcome this problem. The polarity-based
approach used here relies on the desired product being proto-
nated and taken into the aqueous phase such that the orga-
notin species can be removed with the organic phase.
12. See Experimental for the synthesis of o-allyl anilines.
13. For the preparation of o-prenylated anilines see: Cooper,
M. A.; Lucas, M. A.; Taylor, J. M.; Ward, A. D.; Williamson,
N. M. Synthesis 2001, 621.
14. (a) Hamann, L. G.; Higuchi, R. I.; Zhi, L.; Edwards, J. P.;
Wang, X.-N.; Marschke, K. B.; Kong, J. W.; Farmer, L. J.;
Jones, T. K. J. Med. Chem. 1998, 41, 623. (b) Pooley, C. L. F.;
Edwards, J. P.; Goldman, M. E.; Wang, M.-W.; Marschke,
K. B.; Crombie, D. L.; Jones, T. K. J. Med. Chem. 1998, 41,
3461.
15. (a) Raner, K. D.; Ward, A. D. Aust. J. Chem. 1991, 44,
1749. (b) Cooper, M. A.; Francis, C. L.; Holman, J. W.;
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18. To the best ofour knowledge, this represents the first
example ofthe conversion ofcarbamates to ureas via orga-
noaluminum chemistry (see Experimental for procedure). For
an example ofthe analogous conversion ofesters to amides
see: Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett.
1977, 48, 4171.
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