High throughput synthesis of diverse 2,5-disubstituted indoles using titanium carbenoids bearing boronate functionality

Article abstract of DOI:10.1016/j.tet.2007.08.119

A titanium benzylidene complex bearing a boronate group converted resin-bound esters into enol ethers. Suzuki cross-coupling with aryl iodides followed by cleavage with acid completed the solid-phase synthesis of 2,5-disubstituted N-Boc-indoles. Also reported is the use of tert-butyllithium and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane to convert an aryl bromide into an arylboronate in the presence of a dithiane, with simultaneous reduction of an aryl azide to an amine.

Full text of DOI:10.1016/j.tet.2007.08.119

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 901e914
www.elsevier.com/locate/tet
High throughput synthesis of diverse 2,5-disubstituted indoles using
titanium carbenoids bearing boronate functionality
Calver A. Main a, Hanna M. Petersson a, Shahzad S. Rahman b, Richard C. Hartley a,
*
a WestCHEM, Department of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK
b GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
Received 25 June 2007; accepted 30 August 2007
Available online 24 October 2007
Abstract
A titanium benzylidene complex bearing a boronate group converted resin-bound esters into enol ethers. Suzuki cross-coupling with aryl
iodides followed by cleavage with acid completed the solid-phase synthesis of 2,5-disubstituted N-Boc-indoles. Also reported is the use of
tert-butyllithium and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane to convert an aryl bromide into an arylboronate in the presence
of a dithiane, with simultaneous reduction of an aryl azide to an amine.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
(Scheme 2). Treatment with mild acid leads to cleavage from
resin with concomitant cyclisation to generate bicyclic hetero-
aromatic compounds 11 with no trace of the site of attachment
to resin. The switch to a linker cleaved under orthogonal con-
ditions ensures that any unreacted ester 1 remains attached
to the resin and so the products 11 are released in high purity.
Barrett and co-workers introduced the term ‘chameleon catch’
to describe this switch in the nature of a linker.12,13 In theory, it
allows greater diversity to arise from each resin-bound ester 1
as other products would be available from cleaving at the ester
stage (e.g., carboxylic acids, alcohols, etc.).
The discovery of new lead compounds can be achieved
through the synthesis of a large numbers of compounds in
parallel, constituting a compound library, followed by high
throughput screening.1 The members of the library should be di-
verse in structure so as to effectively probe chemical space, but
because chemical space is so large, the inclusion of structural
features that are often associated with biological activity, known
as ‘privileged structures’,2,3 improves the chances of obtaining
a useful lead compound. Once a lead is established, focussed
libraries can then be prepared, which may well contain a range
of privileged structures. The use of solid-phase synthesis facil-
itates the preparation of the libraries as it allows automation.4
Recently, we have developed functionalised titanium carbe-
noids5 to prepare benzofurans 2,6,7 indoles 3,7 benzothiophenes
4,8 quinolines 5,9 cyclic imines10,11 6 and enantiomerically en-
riched piperidines11 7 and 8 from resin-bound esters 1, so that
each ester acts as a precursor to a range of privileged structures
(Scheme 1). The general strategy involves using titanium car-
benoids 9 containing a masked nucleophile to convert acid-
stable, resin-bound esters 1 into acid-sensitive enol ethers 10
R2
R1 R2
R1
O
N
R3
2
3
R2
R1
R1
O
S
N
O
4
1
R2
N
R1
5
R1
N
H
R1
N
R1
H
8
7
6
* Corresponding author. Fax: þ44 141 3304888.
E-mail address: richh@chem.gla.ac.uk (R.C. Hartley).
Scheme 1.
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.08.119

902
C.A. Main et al. / Tetrahedron 64 (2008) 901e914
TiCp2
NuPG
We here report a similar strategy for introducing diversity
acid-labile
linker
in the indole series. The indole moiety is the archetypal
privileged structure, and alkaloids derived from the indole-
containing amino acid, tryptophan, are found widely in
nature.16 These include the human 5-hydroxytryptamine
(5-HT) hormones, serotonin, which is involved in regulation
of the nervous system including neurotransmission, and mela-
tonin, which regulates circadian rhythms and sleep processes.
Although natural indoles are almost invariably 3-substituted,
2-substituted analogues of these hormones are also being
investigated as potential therapeutic agents.17 Other bioactive
2-substituted indoles recently reported include inhibitors of
the proteases involved in coagulation, e.g., factor VIIa
inhibitors,18 antagonists of G-protein-coupled receptors,19
anti-angiogenic compounds20 and inhibitors of endothelin-
converting-enzyme.21 Naturally, new methods for the con-
struction and modification of indole moieties during SPS are
continually being reported.22,23 However, the combination of
intermolecular alkylidenation of an ester group followed by
cyclisation to give an indole is unique to us.
base-labile
linker
R2
O
R1
O
R1
9
R2
O
1
NuPG
10
Merrifield
resin
mild acid
R1
R2
diversity
diversity
diversity
Nu
11
Nu = O, S, NR'
PG = acid-labile protecting group
Scheme 2.
One limitation of our original strategy was that no addi-
tional diversity was added after the switch of the linker, and we
overcame this in the benzofuran series by including a boronate
group in the titanium reagent 12.14 Suzuki cross-coupling be-
tween boronate 13 and a variety of aryl iodides then allowed
access to a range of ketones 14 that cyclised upon deprotection
in strong acid to give 2,5-disubstituted benzofurans 15. Aryl
bromides react under the conditions used to generate our
titanium benzylidene reagents 9, precluding the introduction
of aryl bromide or iodide functionality to the resin by our
method.7 However, immobilisation of the arylboronate compo-
nent is advantageous as aryl halides are more widely and
cheaply available than arylboronates. Therefore, it is surpris-
ing that the aryl halide is almost always the immobilised
coupling partner for cross-couplings in SPS (Scheme 3).15
2. Results and discussion
We chose 5-bromo-2-fluorobenzaldehyde 16 as the starting
material for the synthesis of titanium benzylidene complexes,
as we reasoned that an amino group could be introduced
through SNAr displacement of the fluoride by a suitable nucleo-
phile, the bromide could be replaced by boron through cross-
coupling and the aldehyde would easily be converted into
a dithiane (Scheme 4). Displacement of fluoride by azide pro-
ceeded smoothly to give aldehyde 17, which was then con-
verted into dithiane 18. Reduction of the azide gave aniline
derivative 19. This was converted into carbamate 20, which
was benzylated to give aryl bromide 21. Miyaura cross-cou-
pling then introduced the boronate in high yield, completing
the synthesis of a dithiane 22.24 Treating the dithiane 22 with
freshly prepared Takeda reagent,25 Cp2Ti[P(OEt)3]2, gave a
titanium carbenoid, presumed to be titanium benzylidene 23.
This was used immediately, without isolation, to benzyliden-
ate resin-bound ester 24 (Scheme 5), prepared from Merrifield
resin and contained within MacroKansÔ, which are small
porous polypropylene reactors (0.315 mequiv of resin per
O
R
O
1
3 eq.
O
MOMO
B
O
12
Cp2Ti
THF, reflux
MeO
O
O
B
O
O
R
reactor, using of resin with a loading of 1.97 mequiv gꢀ1
)
13
that allow easy handling of the resin in normal glassware.
Cleavage of the resulting resin-bound enol ether 25 with
acid and cyclisation under our published conditions then
gave boronate 26.26 Alternatively, Suzuki cross-coupling be-
tween the resin-bound arylboronate 25 and aryl iodides to
give enol ethers 27, under conditions optimised previously,14
followed by release and cyclisation gave N-benzyl indoles
28, 29 and 30. Yields are based on the original loading
of the Merrifield resin and so are over five steps. The
products were isolated in high purity without the need for
chromatography.
(i) 5 eq. ArI, 5 eq. CsCO3
4 mol% Pd(PPh3)4
1 eq. H2O, DMF, 80 °C
(ii) 1% TFA-CH2Cl2
(iii) 10% HCl in MeOH
10% HCl
MOMO
O
O
in MeOH
R
R
Ar
14 22-57%
(yield based on resin-loading)
Ar
15 54-100%
Ar= p-MeC6H4, p-MeOC6H4, p-O2NC6H4
R = Me2C=CH, Ph(CH2)2, p-MeOC6H4
Although N-benzyl indoles can be deprotected to give in-
doles,27 N-Boc protecting groups are more easily removed.28
Scheme 3.

C.A. Main et al. / Tetrahedron 64 (2008) 901e914
903
catalysts is used,30 due to the cost of bis(pinacolato)diboron.
Consequently, it seemed better to introduce the boron by lith-
iation and trapping with a borate ester. Under optimised
conditions, treatment of aryl bromide 18 with 3.1 equiv of
tert-butyllithium and quenching with borate 33 gave amine
34 after crystallisation (Scheme 6). In spite of the modest
O
F
O
Br
Br
NaN3, DMF
N3
16
1787%
HS(CH2)2SH
BF3•OEt2, PhMe
1
yield, the H NMR spectrum of the crude mixture following
S
S
LiAlH4
Br
Br
Br
work up appeared to contain no other aromatic compounds.
Two of the three equivalents of tert-butyllithium are required
to convert the aryl bromide moiety into an aryllithium and
to destroy the resulting tert-butyl bromide.31 Organolithiums
are known to attack the terminal nitrogen of aryl azides and
alkyl azides to give 1-aryl-3-alkyltriazenes and 1,3-dialkyltri-
azenes, respectively,32 so dilithiated triazenes 31 and 32 are
likely to be intermediates. 1-Aryl-3-alkyltriazenes decompose
in acid to the corresponding anilines with loss of nitrogen and
generation of an alkyl carbocation, and the reaction is par-
ticularly fast when the carbocation is stabilised.33 A similar
decomposition appears to be induced by the borate 33.
Interestingly, 1,3-disubstituted triazenes have been used as
electrophile-cleavable linkers in solid-phase synthesis, but tri-
substituted triazenes are much more versatile and popular.34
Although the reaction of allyl azide with aryllithiums, fol-
lowed by acid-induced decomposition, is a known method
for preparing anilines,35 the generation of anilines from aryl
azides using tert-butyllithium is new.
THF
S
S
NH2
19 92%
Boc2O,THF
N3
18 91%
S
S
NaH, BnBr
DMF
Br
S
S
NHBoc
20 92%
NBoc
Bn
21 92%
O
O
3 mol%
PdCl2(dppf)
KOAc, DMF
B
B
O
O
O
B
S
O
S
NBoc
Bn
22 89%
4 eq. Cp2Ti[P(OEt)3]2
4 Å MS, THF
O
B
TiCp2
Boc protection of amine 34 gave carbamate 35, which was
then silylated to give a suitable substrate 36 for the generation
of a titanium benzylidene 37 under Takeda conditions. Again,
once generated, the titanium reagent was used immediately
to benzylidenate resin-bound ester 24, and cleavage with con-
comitant cyclisation was achieved under mild conditions7,36 to
give the N-Boc indole 39 (Scheme 7). Suzuki cross-couplings
between the intermediate boronate 38 and a variety of aryl
and heteroaryl iodides gave enol ethers and led to the produc-
tion of 2,5-substituted indoles 40e43 in good purity without
the need for chromatography. However, cross-coupling with
1-iodo-4-nitrobenzene gave a 5:1 mixture of the expected prod-
uct 44 and a compound 45, presumably arising from Buchwald
coupling,37,38 which could not be avoided.
O
NBoc
Bn
23
Scheme 4.
Unfortunately, Miyaura cross-coupling had failed when amine
19 or primary carbamate 20 was the substrate.29 Presumably,
coordination of palladium by the dithiane poisons the catalyst,
and this coordination is prevented by the bulky N-benzylcarba-
mate. In addition to this limitation, we considered that the
Miyaura cross-coupling was expensive, even if a cheaper
O
Ph
O
B
O
B
3 eq. 23
THF
1% TFA
in DCM
(i)
O
Ph
Ph
O
O
(ii)10% TFA
O
24
in DCM
N
N(Boc)Bn
Bn
25
26 34%
R
5 eq.
4 mol% Pd(PPh3)4
1 eq. H2O, DMF, 80 °C
I
R
R
O
Ph
(i)1% TFA
in DCM
Ph
(ii)10% TFA
in DCM
N
Bn
N(Boc)Bn
27
28 R = Me, 45%
29 R = OMe, 26%
30 R = NO2, 34%
Scheme 5. Yields based on original loading of Merrifield resin.

904
C.A. Main et al. / Tetrahedron 64 (2008) 901e914
With good conditions in hand for the alkylidenation, cross-
S
Br
coupling, cleavage sequence, we decided to prepare a library
of 96 indoles 49 (Scheme 8), using smaller amounts of resin
in MiniKansÔ, which are smaller porous polypropylene reac-
tors (93 mequiv of resin per MiniKanÔ, using Merrifield resin
with a loading of 2.0 mequiv gꢀ1). Eight resin-bound esters 46
were prepared and for each ester 13 MiniKansÔ containing
the same resin-bound ester were alkylidenated together to
give enol ethers 47. One MiniKanÔ from each batch was sub-
jected to the cleavage conditions to give the boronates 48 in
good yield and purity, with the exception of 48H, which was
very impure. The identity of the boronate products 48 was
S
N3
18
t
3.1eq BuLi
THF, –78 °C
S
S
S
N
Li
Li
S
N
N
t
t
N
Li
NBu
Li
NBu
31
32
3.3 eq.
O
1
i
THF, –78 °C
B
confirmed by H NMR spectroscopy of the crude material
O Pr
O
33
from cleavage following evaporation of solvent. Enol ether
47G, which has two N-Boc groups, yielded a mono-Boc com-
pound 48G0. It is believed that the N-Boc on the indole is re-
tained, based on the chemical shift of the tert-butyl group and
the obvious stability of the other N-Boc indoles 48AeF. It is
noteworthy that indoles containing Lewis basic sites (48De
G0) could be made using reagent 37, but it would appear
that the 1,2,4-oxadiazole unit has limited stability to the reac-
tion conditions.
O
B
S
S
O
NH2
3439%
Boc2O,THF
O
S
Twelve batches of the eight resin-bound enol ethers 47Ae
H contained in MiniKansÔ were each subjected to Suzuki
cross-coupling with a different aryl or heteroaryl iodide, fol-
lowed by cleavage from resin in separate vessels to give
indoles 49. The crude yields and purities are presented in
Table 1. The library members were identified using reversed
phase HPLC, with diode array UV detection (DAD-UV), evap-
orative light scattering detection (ELSD) and MS analysis.
The purity values for the library members were determined us-
ing summed diode array UV detection (DAD-UV) between the
wavelengths of 210 and 350 nm. In 13 examples (in bold), the
B
O
S
NRBoc
35R= H, 71%
TMSCl, LDA
36R= SiMe3, 98%
4 eq. Cp2Ti[P(OEt)3]2
4 Å MS, THF
O
B
TiCp2
O
NBoc
SiMe3
1
identity of the library members were further confirmed by H
37
NMR spectroscopy following purification by reversed phase
HPLC. It is noteworthy that even when the yield and purity
were low, as was the case for indole 49Fh, sufficient material
Scheme 6.
O
Ph
O
B
O
B
3 eq. 37
1% TFA
in DCM
O
Ph
THF
Ph
O
O
O
24
N
NHBoc
Boc
38
(i) 5 eq. p-O2NC6H4I,
4 mol% Pd(PPh3)4
1 eq.H2O, DMF, 80 °C
(ii) 1% TFA in DCM
39 56%
(i) 5 eq. RI, 4 mol% Pd(PPh3)4
1 eq. H2O, DMF, 80 °C
(ii) 1% TFA in DCM
R
O2N
Ph
Ph
N
Boc
40 R = p-MeC6H4, 53%
41 R = p-MeOC6H4, 54%
42 R = 2-thiophenyl, 62%
43 R = 3-pyridyl, 58%
N
Boc
44
+
68% (44:45 5:1)
O2N
O
Ph
NO2
N
Boc
45
Scheme 7.

C.A. Main et al. / Tetrahedron 64 (2008) 901e914
905
O
R
O
B
O
B
3 eq. 37
1%TFA
in DCM
O
R
THF
R
O
O
O
46
N
NHBoc
Boc
48A 57%
B 61%
C 60%
D 34%
E 42%
F 58%
G' 73%
47
(i) 5eq. ArI, 4 mol% Pd(PPh3)4
1 eq.H2O, DMF, 80°C
(ii) 1% TFA inDCM
Ar
R
H v. impure
N
Boc
49Aa-Hl see Table 1
Resin-bound esters 47
Aryl or heteroaryl iodide (ArI)
O
O
R
NC
I
I
Me2N
MeO
I
I
S
A R = Ph
N
B R = Me
C R = CH2Ph
a
b
c
e
i
I
I
N
S
D R = 3-pyridyl
E R = CH2OPh
N
f
j
OMe
F R =
I
I
N
I
I
HN
N
OMe
g
k
NBoc
G R =
I
I
N
S
N
O
H R =
CN
N
l
d
h
N
N
Scheme 8.
could be obtained for identification in this way, giving confi-
dence that other compounds in the library were correctly
identified by reversed phase HPLC/DAD-UV/ELSD/MS.
Thus, in 79 cases the desired indole was produced (82% suc-
cess). Surprisingly, di-Boc compounds 49G were produced,
and deprotection of the aliphatic amino group did not domi-
nate. As would be expected from the poor quality of boronate
48H, there were few products arising from enol ether 47H.
The enol ethers 47 had efficiently cross-coupled with a wide
range of aryl and heteroaryl iodides including both electron-
rich substrates aec and electron-poor substrates iel. It is not
clear why some derivatives of 3-iodothiophene d were not
formed, but 3-iodopyrazole39 g appears to be a poor substrate
for Suzuki cross-coupling. Indeed, there are no reports of
palladium-catalysed cross-couplings with this substrate in the
literature.
Table 1
Yields of indoles 49 synthesised (unpurified material, purities in parenthesis)
A
B
C
D
E
F
G
H
a
a
b
c
d
e
f
66 (89)
62 (69)
72 (97)
55 (77)
48 (80)
78 (81)
35 (78)
37 (83)
56 (54)
30 (73)
53 (70)
61 (84)
56 (69)
63 (44)
72 (87)
64 (88)
67 (47)
57 (77)
65 (50)
64 (29)
43 (27)
92 (33)
52 (48)
59 (18)
60 (51)
89 (78)
64 (64)
72 (94)
74 (70)
37 (43)
80 (46)
35 (32)
30 (35)
89 (21)
41 (13)
40 (35)
38 (67)
68 (77)
48 (70)
68 (71)
59 (60)
a
a
53 (79)
a
46 (16)
a
a
a
a
60 (66)
65 (41)
57 (36)
50 (70)
58 (21)
85 (64)
81 (86)
45 (91)
62 (91)
76 (8)
39 (24)
39 (18)
71 (20)
a
65 (39)
a
60 (64)
a
a
a
g
h
i
73 (64)
49 (55)
69 (57)
62 (91)
74 (91)
41 (59)
48 (15)
41 (61)
78 (71)
51 (94)
65 (100)
62 (41)
57 (55)
90 (75)
76 (86)
57 (43)
a
39 (84)
18 (12)
a
j
34 (63)
67 (84)
42 (13)
a
a
k
l
a
MW of product not detected.

906
C.A. Main et al. / Tetrahedron 64 (2008) 901e914
3. Conclusion
27], 83 (100). HRMS: 226.9513 and 224.9541. C7H4O81BrN3
ꢃ
requires 226.9518, [Mþ (79Br)] and C7H4O79BrN3 requires
224.9538.
In summary, we have synthesised new titanium carbenoid
reagents bearing a boronate functionality, using a sequence
that involved a novel reduction of an aryl azide with tert-butyl-
lithium. We have demonstrated that this organotitanium re-
agent can be used for the SPS synthesis of 2,5-disubstituted
indoles, and we have exemplified the benzylidenation, Suzuki
cross-coupling, cleavage-cyclisation sequence for introducing
diversity by successfully preparing 79 of the members of a
potential 96-member library of indoles.
4.1.2. 2-(20-Azido-50-bromophenyl)-1,3-dithiane 18
1,3-Propanedithiol (6.0 mL, 51 mmol, 1.2 equiv) was
added to a solution of 2-azido-5-bromo-benzaldehyde 17
(10.0 g, 44.5 mmol, 1 equiv) and BF3$OEt2 (7.0 mL,
55 mmol, 1.2 equiv) in dry toluene (100 mL) under an atmo-
sphere of argon. The reaction mixture was stirred for 2 h.
The reaction was then quenched by adding water and was ex-
tracted into DCM (2ꢂ). Combined organics were washed with
1 M NaOH (2ꢂ), water (2ꢂ), dried (MgSO4) and concentrated
to give 2-(20-azido-50-bromoophenyl)-1,3-dithiane 18 (12.8 g,
40.3 mmol, 91%). A small sample was recrystallised from
isopropanol to give dithiane 18 as yellow needles; mp 162e
164 ꢁC. Rf 0.74 [SiO2, hexaneeDCM (2:1)]. nmax (Golden
Gate)/cmꢀ1: 2093 cmꢀ1 (N3), 2135 (N3), 2898 (CH stretch).
dH (400 MHz, CDCl3): 1.86e1.97 (1H, m, Hax-5), 2.14e
2.21 (1H, m, Heq-5), 2.91 (2H, dt, J 4.1 and 13.7 Hz, Heq-4
and Heq-6), 3.09 (2H, dt, J 2.4 and 13.5 Hz, Hax-4 and Hax-
6), 5.43 (1H, s, H-2), 7.00 (1H, d, J 8.5 Hz, H-30), 7.43 (1H,
dd, J 2.3 and 8.5 Hz, H-40), 7.74 (1H, d, J 2.3 Hz, H-60). dC
(100 MHz, CDCl3): 24.95 (CH2), 32.13 (CH2), 44.29 (CH),
118.18 (C), 119.25 (CH), 132.08 (C), 132.48 (CH), 132.63
4. Experimental
4.1. General
1H and 13C NMR spectra were obtained on a Bruker DPX/
400 spectrometer operating at 400 and 100 MHz, respectively.
All coupling constants are measured in hertz and are uncor-
rected. DEPT was used to assign the signals in the 13C
NMR spectra as C, CH, CH2 or CH3. Mass spectra (MS)
were recorded on a Jeol JMS700 (MStation) spectrometer. In-
frared (IR) spectra were obtained on a PerkineElmer 983
spectrophotometer. A Golden GateÔ attachment that uses a
type IIa diamond as a single reflection element was used so
that the IR spectrum of each compound (solid or liquid) could
be directly detected without any sample preparation. Column
chromatography was carried out on silica gel, 70e230 mesh,
or neutral alumina (Brockmann grade III). Tetrahydrofuran
and diethyl ether were dried over sodium and benzophenone,
and dichloromethane was dried over calcium hydride. The
solid-phase syntheses were carried out using resin derived
from commercially available Merrifield resin with the loadings
described in the text below and contained in IRORI Macro-
KansÔ (porous polypropylene reactors with an internal vol-
ume 2.4 mL, and a pore size of 74 mm) and IRORI
MiniKansÔ (porous polypropylene reactors with an internal
volume 660 mL and a pore size of 74 mm).
ꢃ
(CH), 135.99 (C). m/z (EI): 317 [Mþ (81Br), 20%], 315
ꢃ
ꢃ
[Mþ (79Br), 20], 215 [Mþ (81Br)ꢀN2 and CH2CHCH2SH,
ꢃ
30], 213 [Mþ (79Br)ꢀN2 and CH2CHCH2SH, 30], 83 (100).
79
10
HRMS: 316.9484 and 314.9503. C10H10 81BrN3S2 requires
316.9478 and C10H BrN3S2 requires 314.9500. Microanaly-
sis: C, 38.05; H, 3.13; N, 13.08%. C10H10BrN3S2 requires C,
37.98; H, 3.19; N, 13.29%.
4.1.3. 2-(20-Amino-50-bromophenyl)-1,3-dithiane 19
2-(20-Azido-50-bromophenyl)-1,3-dithiane 18 (9.46 g,
29.9 mmol, 1 equiv) dissolved into dry THF (150 mL) was
added dropwise to a stirred suspension of LiAlH4 (1.70 g,
44.9 mmol, 1.5 equiv) in dry THF (100 mL) under argon and
the mixture was then stirred at rt for 2.5 h. Saturated aqueous
NH4Cl was added carefully under argon to quench the excess
LiAlH4. The reaction mixture was then extracted into Et2O
(2ꢂ), washed with water (2ꢂ), dried (MgSO4) and concen-
trated to give amine 459 as a yellow oil (7.99 g, 27.5 mmol,
92%); Rf 0.32 [SiO2, hexaneeDCM (2:1)]. nmax (Golden
Gate)/cmꢀ1: 1618 (NH2 bend), 2898 (CH stretch), 2931 (CH
stretch), 3353 (NH stretch), 3443 (NH stretch). dH
(400 MHz, CDCl3): 1.72e1.84 (1H, m, Hax-5), 2.01e2.08
(1H, m, Heq-5), 2.80 (2H, dt, J 4.0 and 13.7 Hz, Heq-4 and
Heq-6), 2.94 (2H, dt, J 2.4 and 13.5 Hz, Hax-4 and Hax-6),
4.09 (2H, s, NH2), 5.11 (1H, s, H-2), 6.45 (1H, d, J 8.5 Hz,
H-30), 7.09 (1H, dd, J 2.3 and 8.5 Hz, H-40), 7.34 (1H, d,
J 2.3 Hz, H-60). dC (100 MHz, CDCl3): 24.60 (CH2), 31.05
(CH2), 46.81 (CH), 109.34 (C), 117.48 (CH), 123.91 (C),
4.1.1. 2-Azido-5-bromobenzaldehyde 17
Sodium azide (6.71 g, 103 mmol, 2 equiv) was added to
a stirring solution of 5-bromo-2-flourobenzaldehyde 16
(10.5 g, 51.6 mmol, 1 equiv) in DMSO (100 mL) under argon.
Reaction mixture was stirred at 50 ꢁC for 6 h. The reaction
mixture was then poured into ice water and acidified with con-
centrated HCl. It was then extracted with DCM (2ꢂ), washed
with water (2ꢂ), dried (MgSO4) and concentrated to give
2-azido-5-bromobenzaldehyde 17 as a yellow solid (10.1 g,
44.8 mmol, 87%); mp 87e90 ꢁC (yellow needles from iPrOH).
Rf 0.58 [SiO2, hexaneeDCM (2:1)]. nmax (Golden Gate)/cmꢀ1
:
1670 (CHO), 2129 (N3), 2759 (CH stretch), 2877 (CH stretch).
dH (400 MHz, CDCl3): 7.17 (1H, d, J 8.6 Hz, H-3), 7.71 (1H,
dd, J 2.4 and 8.6 Hz, H-4), 7.98 (1H, d, J 2.4 Hz, H-6), 10.28
(1H, s, CHO). dC (100 MHz, CDCl3): 118.25 (C), 120.75
(CH), 127.94 (C), 131.62 (CH), 137.98 (CH), 141.85 (C),
187.07 (CH). m/z (EI): 227 [Mþ (81Br), 6%], 225 [Mþ
(79Br), 6], 199 [Mþ (81Br)ꢀN2, 27], 197 [Mþ (79Br)ꢀN2,
ꢃ
130.06 (CH), 130.87 (CH), 142.54 (C). m/z (EI): 291 [Mþ
ꢃ
ꢃ
(81Br), 45%], 289 [Mþ (79Br), 45], 216 [Mþ (81Br)ꢀ
81
ꢃCH2CH2CH2SH, 57], 214 [Mþ (79Br)ꢀ CH2CH2CH2SH,
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
57], 83 (100). HRMS: 290.9570 and 288.9598. C10H BrNS2
12

C.A. Main et al. / Tetrahedron 64 (2008) 901e914
907
79
requires 290.9573 and C10H BrNS2 requires 288.9595.
Microanalysis: C, 41.32; H, 4.11; N, 4.70%. C10H12BrNS2
requires C, 41.38; H, 4.17; N, 4.83%.
32.80(CH2), 46.04 (CH), 53.75 (CH2), 81.31 (C), 122.15
(C), 127.93 (CH), 128.84 (CH), 129.32 (CH), 131.43 (CH),
132.04 (CH), 132.82 (CH), 138.18 (C), 138.63 (C), 139.29
12
ꢃ
(C), 155.35 (C]O). m/z (EI): 481 [Mþ (81Br), 5%],
ꢃ
ꢃ
4.1.4. 2-[20-(N-Boc-amino)-50-bromophenyl)]-1,3-dithiane
20
479 [Mþ (79Br), 4], 425 [Mþ (81Br)ꢀCH2]C(CH3)2, 24],
ꢃ
ꢃ
423 [Mþ (79Br)ꢀCH2]C(CH3)2, 22], 380 [Mþ (81Br)ꢀ
ꢃ
ꢃ
A solution of 2-(20-amino-50-bromophenyl)-1,3-dithiane 19
(7.73 g, 26.6 mmol, 1 equiv) and di-tert-butyldicarbonate
(6.39 g, 29.3 mmol, 1.1 equiv) in THF (50 mL) was heated un-
der reflux, under argon, for 15 h. After this time, the reaction
mixture was poured into water and extracted into DCM (2ꢂ).
The combined organics were then washed with water (2ꢂ),
dried (MgSO4) and concentrated. Recrystallisation from
DCMehexane (1:6) gave carbamate 20 as a solid (7.26 g,
18.6 mmol, 70%); mp 127e128 ꢁC. Rf 0.51 [SiO2, hexanee
DCM (2:1)]. nmax (Golden Gate)/cmꢀ1: 1687 cmꢀ1 (C]O),
2929 (CH stretch), 2976 (CH stretch), 3241 (NH stretch),
ꢃCO2C(CH3)3, 28], 378 [Mþ (79Br)ꢀ CO2C(CH3)3, 26], 334
ꢃ
ꢃ
ꢃ
[Mþ (81Br)ꢀCH2]C(CH3)2 and CH2Ph, 60], 332 [Mþ
81
ꢃ
(79Br)ꢀCH2]C(CH3)2 and CH2Ph, 55], 91.1 (100). HRMS:
79
481.0566 and 479.0591. C22H BrNO2S2 requires 481.0569
26
and C22H BrNO2S2 requires 479.0588. Microanalysis: C,
54.75; H, 5.40; N, 3.03; S, 13.42%. C22H26BrNO2S2 requires
C, 54.99; H, 5.45; N, 2.92; S, 13.35%.
26
4.1.6. 2-[20-(N-Boc-N-benzylamino)-50-(400,400,500,500-
tetramethyl-100,300,200-dioxaborolan-200-yl)-phenyl]-1,3-
dithiane 22
t
3323 (NH stretch). dH (100 MHz, CDCl3): 1.54 (9H, s, Bu),
Following the general procedure for Miyaura cross-cou-
pling, a flask charged with PdCl2(dppf) (0.19 g, 0.26 mmol,
3 mol %), KOAc (2.49 g, 25.40 mmol, 3 equiv) and bis(pina-
colato)diboron (2.37 g, 9.31 mmol, 1.1 equiv) was flushed
with argon for 30 min. DMSO (45 mL) and aryl bromide 21
(4.07 g, 8.47 mmol, 1 equiv) were then added, the solution
was degassed for 30 min and then stirred at 80 ꢁC for 26 h.
The reaction mixture was cooled to rt and water was added
to the flask to induce precipitation. The grey solid was col-
lected through filtration and washed several times with water.
The grey solid was then dissolved in EtOAc and a black solid
was removed by filtration through Celite. Removal of solvent
under reduced pressure gave a solid, which was recrystallised
from cyclohexane to give the arylboronate 22 as a pale brown
powder (3.99 g, 89%). Mp 165e168 ꢁC. Rf 0.33 [SiO2,
hexaneeDCM (1:1)]. nmax (Golden Gate)/cmꢀ1: 1689 (C]O),
2928 (CH stretch), 2977 (CH stretch). dH (400 MHz, CDCl3):
1.32 (12H, s, CH3), 1.37 (9H, s, CH3), 1.87e2.20 (2H, m,
H-5axþeq), 2.80e3.05 (4H, m, H-4 and H-6), 4.32 (1H, d,
J 14.5 Hz, PhCHAHB), 5.22 (1H, s, H-2), 5.23 (1H, d,
J 14.8 Hz, PhCHAHB), 6.68 (1H, br s, H-30), 7.21e7.23 (5H,
m, Ar-H), 7.51 (1H, d, J 7.6 Hz, H-40), 8.65 (1H, d,
J 1.0 Hz, H-60). dC (100 MHz, CDCl3, 353 K): 24.98
(CH3), 25.37 (CH2), 28.25 (CH3), 32.57 (CH2), 46.93 (CH),
54.00 (CH2), 80.58 (C), 83.99 (C), 127.33 (CH), 128.32
(CH), 128.85 (CH), 129.08 (CH), 134.94 (CH), 135.88
(CH), 136.28 (C), 138.48 (C), 142.35 (C), 155.23 (C]O).
1.86e1.99 (1H, m, Hax-5), 2.17e2.24 (1H, m, Heq-5), 2.94
(2H, dt, J 3.9 and 13.8 Hz, Heq-4 and Heq-6), 3.09 (2H, dt,
J 2.3 and 13.5 Hz, Hax-4 and Hax-6), 5.23 (1H, s, H-2), 7.26
(1H, s, NH), 7.39 (1H, dd, J 2.3 and 8.8 Hz, H-40), 7.54
(1H, d, J 2.3 Hz, H-60), 7.75 (1H, bd, J 8.1 Hz, H-30). dC
(400 MHz, CDCl3): 25.39 (CH2), 28.74 (CH3), 32.22 (CH2),
48.08 (CH), 81.31 (C), 116.98 (C), 124.65 (CH), 130 (C),
131.60 (CH), 132.38 (CH), 135.83 (C), 153.27 (C]O). m/z
ꢃ
ꢃ
(EI): 391 [Mþ (81Br), 11%], 389 [Mþ (79Br), 10], 335
ꢃ
ꢃ
[Mþ (81Br)ꢀCH2]C(CH3)2, 71], 333 [Mþ (79Br)ꢀCH2]
ꢃ
C(CH3)2, 65], 229 [Mþ (81Br)ꢀCH2]C(CH3)2 and HSCH]
ꢃ
CHCH2SH, 74], 227 [Mþ (79Br)ꢀCH2]C(CH3)2 and
81
20
HSCH]CHCH2SH, 72], 57.1 (100). HRMS: 391.0096.
C15H BrNO2S2 requires 391.0098. Microanalysis: C, 46.34;
H, 5.26; N, 3.57; S, 16.53%. C15H20BrNO2S2 requires C,
46.15; H, 5.16; N, 3.59; S, 16.43%.
4.1.5. 2-[20-(N-Boc-N-benzylamino)-50-bromophenyl)]-1,3-
dithiane 21
NaH (0.38 g, 16 mmol, 1.2 equiv) was added portionwise to
a solution of 2-[20-(N-Boc-amino)-50-bromophenyl)]-1,3-di-
thiane 20 (5.14 g, 13.2 mmol, 1 equiv) and benzyl bromide
(1.90 mL, 1.4 mmol, 1.2 equiv) in DMF (60 mL) at 0 ꢁC under
argon. The reaction mixture was then allowed to warm to rt
and stirred for 3 h. After this time, the reaction mixture was
carefully poured into iced water and extracted into EtOAc
(2ꢂ). The combined organics were washed with water (2ꢂ),
dried (MgSO4) and concentrated. Recrystallisation from
DCMehexane gave N-benzylcarbamate 21 as a yellow solid
(3.37 g, 7.02 mmol, 54%); mp 155e157 ꢁC. Rf 0.46 [SiO2,
hexaneeDCM (2:1),]. nmax (Golden Gate)/cmꢀ1: 1687 cmꢀ1
(C]O), 2904 (CH stretch), 2966 (CH stretch). dH
ꢃ
ꢃ
m/z (EI): 527 (Mþ , 10%), 471 [Mþ ꢀCH2]C(CH3)2, 25],
ꢃ
ꢃ
ꢃ
426 [Mþ ꢀ CO2C(CH3)3, 55], 380 [Mþ ꢀCH2]C(CH3)2
and ꢃCH2Ph], 91 (þCH2Ph, 100). HRMS: 527.2335.
C28H38NO4S2B requires 527.2335. Microanalysis: C, 63.28;
H, 7.22; N, 2.77%. C28H38BNO4S2 requires C, 63.75; H,
7.26; N, 2.66%.
t
(400 MHz, CDCl3): 1.40 (9H, s, Bu), 1.85e1.98 (1H, m,
Hax-5), 2.13e2.18 (1H, m, Heq-5), 2.80e3.02 (4H, m, H-4
and H-6), 4.30 (1H, d, J 14.4 Hz, PhCHAHB), 5.13 (1H, s,
H-2), 5.25 (1H, d, J 14.1 Hz, PhCHAHB), 6.50 (1H, br s,
H-30), 7.20 (1H, dd, J 1.6 and 8.3 Hz, H-40), 7.22e7.35
(5H, m, Ar-H), 7.70 (1H, d, J 2.3 Hz, H-60). dC (100 MHz,
CDCl3): 25.39 (CH2), 28.47 (CH3), 32.49 (CH2),
4.2. Resin-bound enol ether 25
Cp2TiCl2 (0.94 g, 3.8 mmol, 12 equiv), magnesium turn-
ings (0.10 g, 4.1 mmol, 13 equiv, predried at 250 ꢁC over-
˚
night) and freshly activated 4 A molecular sieves (0.25 g)
were heated, gently, under reduced pressure (0.3 mmHg) for

908
C.A. Main et al. / Tetrahedron 64 (2008) 901e914
about 1 min and then placed under argon. Dry THF (5 mL)
was added followed by dry P(OEt)3 (1.3 mL, 7.6 mmol,
24 equiv). After stirring for 3 h at rt, a solution of the dithiane
22 (0.49 g, 0.95 mmol, 3 equiv) in dry THF (4 mL) was added
to the mixture and stirring continued for 15 min. The solution
was added to a flask containing resin-bound ester 24 contained
in a MacroKanÔ [0.315 mequiv prepared from 160 mg of
give indole 28 as a brown oil (55 mg, 45%). Rf 0.71 [SiO2,
hexaneeDCM (1:1)]. nmax (Golden Gate)/cmꢀ1: 1452 (Ar),
1473 (Ar), 2919 (CH stretch). dH (400 MHz, CDCl3): 2.37
(3H, s, CH3), 2.93e3.02 (4H, m, CH2CH2Ph), 5.24 (2H, s,
N-CH2Ph), 6.42 (1H, s, H-3), 6.94 (2H, d, J 8.2 Hz, H-20
and H-60), 7.13 (2H, d, J 8.3 Hz, Ar-H), 7.17e7.28 (9H, m,
Ar-H), 7.34 (1H, dd, J 1.7 and 8.5 Hz, H-6), 7.53 (2H, d,
J 8.1 Hz, H-30 and H-50), 7.78 (1H, d, J 1.5 Hz, H-4). dC
(100 MHz, CDCl3): 21.04 (CH3), 28.68 (CH2), 34.91 (CH2),
46.42 (CH2), 100.03 (CH), 109.46 (CH), 118.27 (CH),
120.72 (CH), 125.90 (CH), 126.16 (CH), 127.14 (CH),
127.29 (CH), 128.33 (CH), 128.44 (CH), 128.52 (C), 128.77
(CH), 129.31 (CH), 133.03 (C), 135.74 (C), 136.61 (C),
137.77 (C), 139.75 (C), 141.10 (C), 141.15 (C). m/z (EI):
Merrifield resin with a loading of 1.97 mequiv (chloride) gꢀ1
]
and preswollen in THF (6 mL) under argon. After 17 h the re-
actor was removed from the flask and washed with THF (5ꢂ)
then alternately with MeOH and DCM (5ꢂ) and finally with
MeOH and Et2O. The reactor containing the resin-bound
enol ether 25 was then dried under vacuum.
ꢃ
ꢃ
ꢃ
4.2.1. N-Benzyl-2-phenethyl-5-(40,40,50,50-tetramethyl-10,30-
dioxaborolan-20-yl)indole 26
401 (Mþ , 83), 310 (Mþ ꢀ CH2Ph, 100). HRMS: 401.2148.
C30H27N requires 401.2144.
A MacroKanÔ containing the resin-bound enol ether 25
(0.315 mequiv) was shaken with trifluoroacetic acid (1%) in
DCM (5 mL) for 1.5 h. The solution was removed and the
MacroKanÔ was washed with DCM (3ꢂ). Combined or-
ganics were concentrated under reduced pressure. The residue
was placed under argon, dissolved in dry DCM (5 mL) and
stirred at 0 ꢁC under argon. Trifluoroacetic acid (0.5 mL,
6.5 mmol) was added dropwise and the mixture was allowed
to warm to rt and then stirred for 2 h. After this time, the
reaction mixture was poured into saturated aqueous sodium
bicarbonate and extracted into DCM (2ꢂ). The combined
organics were washed with saturated aqueous sodium bicar-
bonate (2ꢂ), dried over magnesium sulfate and concentrated
under reduced pressure to give indole 26 as a brown oil
(46 mg, 34%). Rf 0.25 [SiO2, hexaneeDCM (1:1)]. nmax
(Golden Gate)/cmꢀ1: 2926 cmꢀ1 (CH stretch), 1351 (BeO).
dH (400 MHz, CDCl3): 1.35 (12H, s, 4ꢂCH3), 2.96 (4H, s,
CH2CH2Ph), 5.25 (2H, s, CH2, NCH2Ph), 6.40 (1H, s, H-3),
6.89 (2H, dd, J 1.8 and 8.0 Hz, Ar-H), 7.10e7.26 (9H, m,
Ar-H), 7.58 (1H, dd, J 1.0 and 8.2 Hz, H-6), 8.12 (1H, s, H-
4). dC (100 MHz, CDCl3): 24.88 (CH3), 28.63 (CH2), 34.82
(CH2), 46.28 (CH2), 83.33 (C), 100.36 (CH), 108.73 (CH),
125.83 (CH), 126.13 (CH), 127.25 (CH), 127.78 (CH),
128.33 (CH), 128.40 (CH), 128.73 (CH), 137.65 (C), 139.20
4.2.3. N-Benzyl-5-(40-methoxyphenyl)-2-phenethylindole 29
In the same way, resin-bound enol ether 25 (0.315 mequiv)
and 4-iodoanisole (370 mg, 1.6 mmol) yielded indole 29 as
a brown oil (34 mg, 26%). Rf 0.50 [SiO2, hexaneeDCM
(1:1)]. nmax (Golden Gate)/cmꢀ1: 1453 cmꢀ1 (Ar), 1474
(Ar), 2936 (CH stretch). dH (400 MHz, CDCl3): 2.85e2.95
(4H, m, CH2CH2Ph), 3.74 (3H, s, OCH3), 5.17 (2H, s, Ne
CH2Ph), 6.34 (1H, s, H-3), 6.85e6.89 (4H, m, Ar-H), 7.04e
7.20 (9H, m, Ar-H), 7.23 (1H, dd, J 1.7 and 8.5 Hz, H-6),
7.48 (2H, m, Ar-H), 7.66 (1H, d, J 1.5 Hz, H-4). dC
(100 MHz, CDCl3): 28.68 (CH2), 34.88 (CH2), 46.40 (CH2),
55.29 (CH3), 99.94 (CH), 109.46 (CH), 114.02 (CH), 118.00
(CH), 120.57 (CH), 125.88 (CH), 126.16 (CH), 127.28
(CH), 128.22 (CH), 128.33 (CH), 128.43 (CH), 128.52 (C),
128.77 (CH), 132.75 (C), 135.26 (C), 136.41 (C), 137.76
ꢃ
(C), 141.09 (C), 141.14 (C), 158.34 (C). m/z (EI): 417 (Mþ ,
ꢃ
ꢃ
61), 326 (Mþ ꢀ CH2Ph, 100), 91 (þCH2Ph, 31). HRMS:
417.2093. C30H27NO required 417.2095.
4.2.4. N-Benzyl-5-(40-nitrophenyl)-2-phenethylindole 30
In the same way, resin-bound enol ether 25 (0.315 mequiv)
and 4-iodonitrobenzene (0.45 g, 1.6 mmol) yielded indole 30
as a brown oil (45 mg, 34%). Rf 0.47 [SiO2, hexaneeDCM
(1:1)]. nmax (Golden Gate)/cmꢀ1: 1338 cmꢀ1 (NO2), 1453
(Ar), 1512 (NO2), 3024 (CH stretch). dH (400 MHz, CDCl3):
2.98e3.05 (4H, m, CH2CH2Ph), 5.29 (2H, s, NeCH2Ph),
6.40 (1H, s, H-3), 6.95 (2H, d, J 6.6 Hz, Ar-H), 7.15 (2H, d,
J 6.9 Hz, Ar-H), 7.16e7.31 (7H, m, Ar-H), 7.37 (1H, dd, J
1.7 and 8.5 Hz, H-6), 7.74 (2H, d, J 8.8 Hz, Ar-H), 7.84
(1H, d, J 1.6 Hz, H-4), 8.24 (2H, d, J 8.8 Hz, H-30 and H-
50). dC (100 MHz, CDCl3): 28.60 (CH2), 34.73 (CH2), 46.47
(CH2), 100.39 (CH), 109.96 (CH), 119.12 (CH), 120.59
(CH), 123.97 (CH), 125.80 (CH), 126.24 (CH), 127.43
(CH), 128.29 (CH), 128.46 (CH), 128.65 (C), 128.83 (CH),
130.31 (C), 137.34 (C), 137.47 (C), 140.88 (C), 141.98 (C),
ꢃ
(C), 140.56 (C). 141.13 (C). m/z (EI): 437 (Mþ , 42%), 346
ꢃ
ꢃ
ꢃ
(Mþ ꢀ CH2Ph, 100). HRMS: 437.2524 (Mþ ). C29H BNO2
11
32
requires 437.2526.
4.2.2. N-Benzyl-5-(40-methylphenyl)-2-phenethylindole 28
Pd(PPh3)4 (15 mg, 4 mol %) was added to a stirring sus-
pension of the resin-bound enol ether 25 (0.315 mequiv)
contained in a MacroKanÔ, Cs2CO3 (0.54 g, 1.7 mmol,
5.3 equiv) and 4-iodotoluene (350 mg, 1.6 mmol, 5.1 equiv),
in degassed DMF (15 mL) with H2O (5.6 mL, 1 equiv) under
argon. The suspension was stirred at 80 ꢁC for 17 h. The mix-
ture was allowed to cool and the MacroKanÔ was separated
from the reaction mixture and washed with 9:1 DMFeH2O
(3ꢂ), alternately with MeOH and DCM (3ꢂ) and finally
with MeOH and Et2O. The MacroKanÔ containing resin-
bound enol ether 27 was then dried under vacuum before being
cleaved, in the same way as for the synthesis of boronate 26 to
ꢃ
146.13 (C), 149.11 (C). m/z (EI): 432 (Mþ , 44%), 341
ꢃ
ꢃ
ꢃ
ꢃ
(Mþ ꢀ CH2Ph, 100), 295 (Mþ ꢀ CH2Ph and NO2, 13), 91
(þCH2Ph, 51). HRMS: 433.1917. C29H24N2O2 requires
433.1916.

C.A. Main et al. / Tetrahedron 64 (2008) 901e914
909
ꢃ
ꢃ
ꢃ
4.2.5. 2-[20-Amino-50-(400,500-tetramethyl-100,300,200-
dioxaborolan-200-yl)]-1,3-dithiane 34
m/z (EI): 437 (Mþ , 6%), 380 (71), 274 (Mþ , ꢀ C(CH3)3 and
HSCH]CHCH2SH, 100). HRMS: 437.1866. C21H32O4NS2B
requires 437.1867.
tert-Butyllithium (69.5 mL, 1.7 M, 118 mmol) was added
dropwise over a period of 1 h 45 min to a cooled (ꢀ80 to
ꢀ89 ꢁC) stirred solution of aryl azide 18 (12.1 g,
38.1 mmol) in dry THF (120 mL) under argon ensuring the
temperature did not exceed ꢀ80 ꢁC. The reaction mixture
was stirred for 15 min at ꢀ80 ꢁC and 2-isopropoxy-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane (25.6 mL, 126 mmol) was
added dropwise over 45 min and the resulting mixture was
stirred for 1 h 30 min before being allowed to warm to rt
and stirred overnight. Water buffered to pH 7 was added and
the mixture extracted with DCM (3ꢂ). The combined organics
were washed with water and then with brine (3ꢂ) and dried
(MgSO4). Removal of solvent under reduced pressure gave
a dark brown oil. Crystallisation from pentane and ethyl ace-
tate gave the boronate 34 as a brown solid (4.97 g, 39%).
Mp 190e193 ꢁC. Rf 0.70 [SiO2, DCMehexane]. nmax (Golden
Gate)/cmꢀ1: 1607 (Ar), 3402 (NH2). dH (400 MHz, CDCl3):
1.23 (12H, s, CH3), 1.82e1.99 (1H, m, Hax-5), 2.09e2.21
(1H, m, Heq-5), 2.83 (2H, td, J 4.0 and 13.0 Hz, Heq-4 and
Heq-6), 3.01 (2H, dt, J 2.0 and 13.0 Hz, Hax-4 and Hax-6),
4.40 (2H, br s, NH2), 5.26 (1H, s, H-2), 6.57 (1H, d, J
8.1 Hz, H-30), 7.48 (1H, dd, J 1.4 and 8.1 Hz, H-40), 7.63
(1H, d, J 1.3 Hz, H-60). dC (100 MHz, CDCl3): 24.89 (CH3),
25.29 (CH2), 32.00 (CH2), 49.97 (CH), 83.40 (C), 116.16
(CH), 121.50 (C), 136.21 (CH), 136.29 (CH), 147.82 (C).
4.2.7. 2-[20-Aminosilylcarbamate-50-(400,500-tetramethyl-
100,300,200-dioxaborolan-200-yl)]-1,3-dithiane 36
A solution of lithium diisopropylamide (1.80 mL, 2.0 M,
3.4 mmol) was added dropwise to a cooled stirred solution
of carbamate 35 (1.22 g, 2.8 mmol) and TMSCl (0.42 mL,
3.4 mmol) in THF (30 mL) at ꢀ78 ꢁC under an inert atmo-
sphere of argon. The reaction mixture was then allowed to
warm to rt over 45 min and was allowed to stir for a further
1 h at rt. After this time, the solvent was removed in vacuo
and ether (30 mL) was added. The resulting white solid was
filtered off and the ethereal solution concentrated to furnish
target N-silylcarbamate 36 as an off-white solid (1.40 g,
98%). dH (400 MHz, CDCl3): 0.24 (9H, s, SieCH3), 1.33
t
(12H, s, CH3), 1.54 (9H, s, Bu), 1.92e2.05 (1H, m, Hax-5),
2.14e2.22 (1H, m, Heq-5), 2.88e3.07 (4H, m, Heq-4, Heq-6,
Hax-4 and Hax-6), 5.21 (1H, s, H-2), 6.94 (1H, d, J 7.7 Hz,
H-30), 7.65 (1H, dd, J 1.3 and 7.7 Hz, H-40), 8.06 (1H, d, J
1.3 Hz, H-60). dC (100 MHz, CDCl3): 0.60 (CH3), 23.52
(CH3), 23.82 (CH2), 27.05 (CH3), 30.59 (CH2), 48.18 (CH),
79.26 (C), 82.39 (C), 119.35 (C), 126.95 (C), 134.27 (CH),
ꢃ
134.58 (CH), 138.28 (C), 151.41 (C). m/z (EI): 509 (Mþ ,
ꢃ
ꢃ
ꢃ
ꢃ
3%), 452 [(Mþ ꢀ C(CH3)3, 55)], 408 [(Mþ ꢀ C(CH3)3 and
ꢃ
ꢃ
CO2, 60)], 346 (Mþ , ꢀ C(CH3)3 and HSCH]CHCH2SH,
ꢃ
m/z (EI): 337 (Mþ , 79%), 262 (100). HRMS: 337.1338.
100). HRMS: 509.2263. C24H40O4NS2BSi requires 509.2261.
C16H24O2NS2B requires 337.1341. Microanalysis: C, 57.02;
H, 7.17; N, 4.22%. C16H24O2NS2B requires C, 56.97; H,
7.17; N, 4.15%.
4.3. Resin-bound enol ether 38
Resin-bound enol ether was prepared in the same way as
resin-bound enol ether 25, but using dithiane 36 instead of di-
thiane 22 with resin-bound ester 24 contained in a MacroKanÔ
[0.325 mequiv prepared from 170 mg of Merrifield resin with
a loading of 1.91 mequiv (chloride) gꢀ1].
4.2.6. 2-[20-tert-Butoxycarboxyamino-50-(400,500-tetramethyl-
100,300,200-dioxaborolan-200-yl)]-1,3-dithiane 35
A solution of amine 34 (5.81 g, 17.2 mmol) in dry THF
(150 mL) and (Boc)2O (7.89 g, 36.2 mmol) was heated under
reflux for 12 h under argon. After this time an additional
equivalent of (Boc)2O (3.75 g) was added and the reaction
mixture stirred at reflux for a further 24 h. The reaction mix-
ture was then allowed to cool to rt and quenched with water.
The mixture was extracted with DCM (2ꢂ) and the combined
organics were washed with water (2ꢂ) and dried (MgSO4).
Removal of solvent under reduced pressure gave a yellow
solid. Column chromatography eluting with hexaneeEtOAc
(4:1) gave carbamate 35 as a pale yellow solid (5.41 g,
71%). Mp 99e101 ꢁC. Rf 0.45 [SiO2, hexaneeEtOAc (4:1)].
nmax (Golden Gate)/cmꢀ1: 1366 (BeO), 1478 (Ar), 1682
(C]O). dH (400 MHz, CDCl3): 1.32 (12H, s, CH3), 1.54
4.3.1. N-Boc-2-phenylethyl-5-(400,500-tetramethyl-100,300,200-
dioxaborolan-200-yl)]-indole 39
A MacroKanÔ containing the resin-bound enol ether 25
(0.325 mequiv) was shaken with trifluoroacetic acid (1%) in
DCM (5 mL) for 1.5 h. The solution was removed and the re-
actor was washed with DCM (3ꢂ). Combined organics were
concentrated under reduced pressure to give indole 39 as a pur-
ple solid (81 mg, 56%). Mp 101e104 ꢁC. Rf 0.76 [SiO2,
DCM]. nmax (Golden Gate)/cmꢀ1: 1734 (C]O), 2976 (CH).
dH (400 MHz, CDCl3): 1.36 (12H, s, CH3), 1.68 (9H, s,
tBu), 3.01 (2H, t, J 8.4 Hz, H-20), 3.32 (2H, t, J 8.4 Hz, H-
10), 6.33 (1H, s, H-3), 7.18e7.29 (5H, m, Ar-H), 7.69 (1H,
dd, J 0.9 and 8.4 Hz, H-6), 7.92 (1H, d, J 0.9 Hz, H-4), 8.04
(1H, d, J 8.4 Hz, H-7). dC (100 MHz, CDCl3): 24.93 (CH3),
28.27 (CH3), 31.76 (CH2), 35.20 (CH2), 83.65 (C), 83.95
(C), 107.64 (CH), 114.94 (CH), 126.00 (CH), 127.06 (CH),
128.38 (CH), 128.43 (CH), 128.90 (C), 129.74 (CH), 138.69
t
(9H, s, Bu), 1.91 (1H, ttd, J 3.0, 12.5 and 14.1 Hz, Hax-5),
2.17 (1H, ttd, J 2.3, 3.9 and 14.2 Hz, Heq-5), 2.93 (2H, ddd,
J 3.3, 3.9 and 14.4, Heq-4 and Heq-6), 3.06 (2H, ddd, J 2.3,
12.5 and 14.4 Hz, Hax-4 and Hax-6), 5.34 (1H, s, H-2), 7.69 (1H,
br s, NH), 7.71 (1H, dd, J 1.4 and 8.3 Hz, H-40), 7.78 (1H, d, J
1.4 Hz, H-60), 7.96 (1H, d, J 8.3 Hz, H-30). dC (100 MHz,
CDCl3): 24.86 (CH3), 25.17 (CH2), 28.40 (CH3), 31.93 (CH2),
49.52 (CH), 80.59 (C), 83.73 (C), 85.17 (CH), 135.61
(CH), 135.91 (CH), 139.62 (C), 146.75 (C), 152.75 (C).
ꢃ
(C), 141.47 (C), 141.59 (C), 150.52 (C). m/z (EI): 447 (Mþ ,
ꢃ
19%), 391 (Mþ ꢀCH2]C(CH3)2, 44), 300 (82), 83 (100).
HRMS: 447.2577. C27H34O4NB requires 447.2571.

910
C.A. Main et al. / Tetrahedron 64 (2008) 901e914
4.3.2. N-Boc-5-(40-methylphenyl)-2-(200-phenylethyl)indole
40
dC (100 MHz, CDCl3): 28.25 (CH3), 31.76 (CH2), 35.12
(CH2), 84.05 (C), 107.45 (CH), 115.90 (CH), 117.08 (CH),
121.76 (CH), 122.61 (CH), 124.08 (CH), 126.03 (CH),
127.94 (CH), 128.40 (CH), 128.42 (CH), 129.30 (C), 129.80
(C), 135.99 (C), 141.39 (C), 142.56 (C), 145.16 (C), 150.41
Pd(PPh3)4 (14.4 mg, 4 mol %) was added to a stirring sus-
pension of resin-bound enol ether 25 (0.325 mequiv) con-
tained in a MacroKanÔ, Cs2CO3 (511 mg, 1.5 mmol,
4.6 equiv) and 4-iodotoluene (338 mg, 1.55 mmol, 4.8 equiv),
in degassed DMF (15 mL) with H2O (5.6 mL, 0.31 mmol,
0.96 equiv) under argon. The mixture was stirred at 80 ꢁC
for 5 h. Cleavage in the same way as for indole 39 gave indole
40 as a brown solid (74.1 mg, 53%). Mp 75e78 ꢁC. Rf 0.76
[SiO2, DCM]. nmax (Golden Gate)/cmꢀ1: 1468 (Ar), 1731
(C]O), 2929 (CH), 2077 (CH), 3025 (Ar-H). dH (400 MHz,
ꢃ
ꢃ
(C). m/z (EI): 403 (Mþ , 43%), 347 (Mþ ꢀCH2]C(CH3)2,
67], 212 (100). HRMS: 403.1607. C25H25O3NS requires
403.1606.
4.3.5. N-Boc-2-(20-phenylethyl)-5-(300-pyridyl)indole 43
In the same way, but using 3-iodopyridine (312 mg) as the
aryl iodide in the Suzuki cross-coupling gave indole 43 as its
TFA salt (105 mg) as a dark brown solid. A portion of the salt
(40.0 mg) was treated with NaHCO3 and extracted into DCM.
The combined organics were concentrated under reduced pres-
sure to give the indole 43 (27.6 mg, 58%) as a brown oil. nmax
(KBr)/cmꢀ1: 1496 (Ar), 1733 (C]O), 2854 (CH), 2974 (CH).
dH (400 MHz, CDCl3): 1.64 (9H, s, tBu), 2.98 (2H, t, J 7.8 Hz,
CH2Ph), 3.30 (2H, t, J 7.8 Hz, CH2CH2Ph), 6.35 (1H, s, H-3),
7.12e7.23 (5H, m, Ph), 7.40 (1H, dd, J 2.0 and 8.8 Hz, H-6),
7.58 (1H, d, J 2.0 Hz, H-4), 7.84e7.87 (1H, m, H-500), 8.12
(1H, d, J 8.8 Hz, H-7), 8.52 (1H, d, J 8.6 Hz, H-400), 8.68
(1H, d, J 2.2 and 8.6 Hz, H-600), 9.04 (1H, d, J 2.2 Hz,
H-200). dC (100 MHz, CDCl3): 27.25 (CH3), 30.74 (CH2),
34.12 (CH2), 83.15 (C), 106.41 (CH), 115.13 (CH), 117.30
(CH), 121.51 (CH), 125.03 (CH), 126.74 (CH), 127.39 (C),
128.14 (CH), 128.31 (CH), 130.21 (C), 137.14 (C), 139.21
(CH), 140.31 (CH), 141.72 (C), 140.07 (C), 142.73
t
CDCl3): 1.63 (9H, s, Bu), 2.33 (3H, s, CH3), 2.97 (2H, t,
J 8.4 Hz, CH2Ph), 3.28 (2H, t, J 8.4 Hz, CH2CH2Ph), 6.32
(1H, s, H-3), 7.14e7.27 (5H, m, Ar-H), 7.22 (2H, d,
J 8.8 Hz, Ar-H), 7.40 (1H, dd, J 2.0 and 8.8 Hz, H-6), 7.47
(2H, d, J 8.8 Hz, Ar-H), 7.56 (1H, d, J 2.0 Hz, H-4), 8.03
(1H, d, J 8.8 Hz, H-7). dC (100 MHz, CDCl3): 21.12 (CH3),
28.32 (CH3), 32.52 (CH2), 35.25 (CH2), 83.93 (C), 107.57
(CH), 115.80 (CH), 118.06 (CH), 122.71 (CH), 126.07
(CH), 127.14 (CH), 128.45 (CH), 128.47 (CH), 129.78
(CH), 129.87 (C), 135.85 (C), 135.91 (C), 136.49 (C),
138.84 (C), 141.52 (C), 142.31 (C), 150.62 (C). m/z (EI):
ꢃ
ꢃ
411 (Mþ , 34%), 355 (Mþ ꢀCH2]C(CH3)2, 56), 264 (95),
290 (100). HRMS: 411.2199. C28H29O2N requires 411.2198.
4.3.3. N-Boc-5-(40-methoxyphenyl)-2-(200-phenylethyl)indole
41
ꢃ
In the same way, but using 4-iodoanisole (365 mg) as the
aryl iodide in the Suzuki cross-coupling gave indole 41 as a
dark brown solid (74.3 mg, 54%). Mp 80e83 ꢁC. nmax (Golden
Gate)/cmꢀ1: 1468 (Ar), 1731 (C]O), 2929 (CH). dH
(CH), 143.42 (C), 149.93 (C). m/z (EI): 398 (Mþ , 21%),
ꢃ
342 [Mþ ꢀCH2]C(CH3)2, 48], 251 (65), 207 (100). HRMS:
398.1996. C26H26O2N2 requires 398.1994.
t
(400 MHz, CDCl3): 1.61 (9H, s, Bu), 2.95 (2H, t, J 7.8 Hz,
4.3.6. N-Boc-5-(400-nitrophenyl)-2-(20-phenylethyl)indole 44
and 1-[20-(N-Boc- 400-nitrophenylamino)-50-(4000-nitro-
CH2Ph), 3.26 (2H, t, J 7.8 Hz, CH2CH2Ph), 3.76 (3H, s,
OCH3), 6.29 (1H, s, H-3), 6.89 (2H, d, J 2.0 Hz, H-30 and
H-50), 7.09e7.25 (5H, m, Ph), 7.34 (1H, dd, J 2.0 and 8.8 Hz,
H-6), 7.48 (2H, d, J 2.0 Hz, H-20 and H-60), 7.52 (1H, d, J
2.0 Hz, H-4), 8.03 (1H, d, J 8.8 Hz, H-7). dC (100 MHz,
CDCl3): 28.31 (CH3), 31.83 (CH2), 35.24 (CH2), 55.40
(CH3), 82.87 (C), 107.43 (CH), 114.20 (CH), 115.79 (CH),
117.79 (CH), 122.66 (CH), 126.05 (CH), 128.26 (CH),
128.43 (CH), 128.64 (CH), 128.79 (C), 133.27 (C), 134.51
(C), 134.58 (C), 140.43 (C), 141.22 (C), 149.51 (C), 157.70
phenyl)phenyl]-4-phenylbutan-2-one 45
In the same way, but using 1-iodo-4-nitrobenzene (391 mg)
and heating at 80 ꢁC for only 2 h in the Suzuki cross-coupling,
gave a 5:1 mixture of indole 44 and ketone 45 (97 mg, 68%)
after cleavage. Pure samples of each compound were obtained
by chromatography (DCM). Indole 44 was isolated as a yellow
solid. Rf 0.85 [SiO2, DCM]. nmax (Golden Gate)/cmꢀ1: 1341
(NO2), 1516 (NO2), 1595 (Ar), 1734 (C]O), 2926 (CH),
2968 (CH). dH (400 MHz, CDCl3): 1.63 (9H, s, CH3), 2.97
(2H, t, J 7.9 Hz, CH2Ph), 3.28 (2H, t, J 7.9 Hz, CH2CH2Ph),
6.33 (1H, s, H-3), 7.13e7.22 (5H, m, Ar-H), 7.41 (1H, dd, J
1.9 and 8.7 Hz, H-6), 7.61 (1H, d, J 1.7 Hz, H-4), 7.67 (2H,
d, J 8.8 Hz, H-200 and H-600), 8.09 (1H, d, J 8.7 Hz, H-7),
8.19 (2H, d, J 8.8 Hz, H-300 and 500). dC (100 MHz, CDCl3):
28.30 (CH3), 31.77 (CH2), 35.16 (CH2), 84.39 (C), 107.50
(CH), 116.57 (CH), 119.43 (CH), 122.73 (CH), 124.10
(CH), 126.14 (CH), 128.38 (CH), 127.71 (CH), 128.42
(CH), 130.03 (C), 133.26 (C), 136.93 (C), 141.29 (C),
143.04 (C), 146.67 (C), 148.24 (C), 150.34 (C). m/z (EI):
ꢃ
(C). Mass (m/z) LRMS (EIþ): 427 (Mþ , 52%), 371
ꢃ
(Mþ ꢀCH2]C(CH3)2, 87), 280 (100). HRMS: 427.2148.
C28H29O3N requires 427.2147.
4.3.4. N-Boc-2-(20-phenylethyl)-5-(200-thiophenyl)indole 42
In the same way, but using 2-iodothiophene (322 mg) as the
aryl iodide in the Suzuki cross-coupling gave indole 42 as
a dark brown solid (81 mg, 62%). Mp 108e110 ꢁC. nmax
(Golden Gate)/cmꢀ1: 1470 (Ar), 1726 (C]O), 2854 (CH),
t
2925 (CH). dH (400 MHz, CDCl3): 1.68 (9H, s, Bu), 3.03
ꢃ
ꢃ
(2H, t, J 8.0 Hz, CH2Ph), 3.33 (2H, t, J 8.0 Hz, CH2CH2Ph),
6.35 (1H, s, H-3), 7.02e7.08 (1H, m, H-400), 7.18e7.31 (7H,
m, H-500, H-300 and Ph), 7.51 (1H, dd, J 2.0 and 8.8 Hz, H-
6), 7.66 (1H, d, J 2.0 Hz, H-4), 8.07 (1H, d, J 8.8 Hz, H-7).
442 (Mþ , 16%), 386 (Mþ ꢀCH2]C(CH3)2, 63), 295 (86),
57 (100). HRMS: 442.1893. C27H26O4N2 requires 442.1893.
Ketone 45 was isolated as an orange solid. Rf 0.48 [SiO2,
DCM]. nmax (Golden Gate)/cmꢀ1: 1342 (NO2), 1517 (NO2),

C.A. Main et al. / Tetrahedron 64 (2008) 901e914
911
1592 (Ar), 1717 (C]O), 2924 (CH). dH (400 MHz, CDCl3):
4.4.4. N-Boc-2-(30-phenylpropyl)-5-(400,500-tetramethyl-
1.38 (9H, s, CH3), 2.71 (4H, m, CH2CH2Ph), 3.46 (1H, d, J
15.7 Hz), 3.54 (1H, d, J 15.7 Hz), 7.03e7.21 (5H, m, Ar-H),
7.25 (1H, d, J 8.2 Hz, H-30), 7.29 (2H, d, J 9.3 Hz, H-200 and
H-600), 7.41 (1H, d, J 2.2 Hz, H-60), 7.55 (1H, dd, J 2.2 and
8.2 Hz, H-40), 7.67 (2H, d, J 8.8 Hz, H-2000 and H-6000), 8.04
(2H, d, J 9.3 Hz, H-300 and H-500), 8.25 (2H, d, J 8.8 Hz,
H-3000 and H-5000). dC (100 MHz, CDCl3): 28.09 (CH3), 29.60
(CH2), 45.18 (CH2), 83.28 (C), 123.48 (CH), 124.21 (CH),
124.31 (CH), 126.31 (CH), 127.54 (CH), 127.99 (CH),
128.28 (CH), 128.56 (CH), 130.59 (CH), 131.27 (CH),
133.50 (C), 138.96 (C), 140.48 (C), 140.59 (C), 143.70 (C),
146.03 (C), 147.45 (C), 147.64 (C), 152.65 (C), 205.36 (C).
m/z (FABþ): 582 (MþHþ, 22%), 526 [(MþH)þꢀ
CH2]C(CH3)2, 40], 482 (58), 481 (32), 59 (100). HRMS:
582.2240. C33H32O7N3 requires MþHþ, 582.2240.
100,300,200-dioxaborolan-200-yl)indole 48C
In the same way, one MiniKanÔ containing resin-bound
enol ether 47C (93 mequiv) gave indole 48C (25.7 mg,
60%). dH (400 MHz, CDCl3): 1.33 (12H, s, CH3), 1.66 (9H,
t
s, Bu), 2.04 (2H, qn, J 7.4 Hz, CH2CH2CH2), 2.73 (2H, t,
J 7.4 Hz, CH2CH2CH2Ph), 3.03 (2H, t, J 7.4 Hz, CH2Ph),
7.19e7.29 (5H, m, Ar-H), 6.34 (1H, s, H-3), 7.67 (1H, dd,
J 1.6 and 8.4 Hz, H-6), 7.93 (1H, d, J 1.6 Hz, H-4), 8.08
(1H, d, J 8.4 Hz, H-7).
4.4.5. N-Boc-2-[20-(300-pyridyl)]-5-(4000,5000-tetramethyl-
1000,3000,2000-dioxaborolan-2000-yl)indole 48D
In the same way, one MiniKanÔ containing resin-bound
enol ether 47D (93 mequiv) gave indole 48D (24.2 mg,
t
58%). dH (400 MHz, DMSO-d6): 1.21 (9H, s, Bu), 1.24
(12H, s, CH3), 2.76 (2H, t, J 7.2 Hz, CH2CH2), 3.17 (2H, t,
J 7.2 Hz, CH2CH2), 6.32 (1H, s, H-3), 7.12 (1H, dd, J 1.6
and 8.4 Hz, H-6), 7.22 (1H, d, J 1.6 Hz, H-4), 7.25 (1H, br
dd, J 4.8 and 7.7 Hz, H-500), 7.62 (1H, d, J 8.4 Hz, H-7),
7.67 (1H, br d, J 7.8 Hz, H-400), 8.41 (1H, br s, H-200), 8.43
(1H, br d, J 4.7 Hz, H-600).
4.4. Library synthesis
4.4.1. Resin-bound enol ether 47
Cp2TiCl2 (3.623 g, 14.5 mmol, 12 equiv), magnesium turn-
ings (0.391 g, 15.9 mmol, 13 equiv, predried at 250 ꢁC over-
˚
night) and freshly activated 4 A molecular sieves (703 mg)
were heated, gently, under reduced pressure (0.3 mmHg) for
about 1 min and then placed under argon. Dry THF (20 mL)
was added followed by dry P(OEt)3 (5.2 mL, 29 mmol,
24 equiv). After stirring for 3 h at rt, a solution of the dithiane
36 (1.85 g, 3.6 mmol, 3 equiv) in dry THF (20 mL) was added
to the mixture and stirring continued for 15 min. After this
time, 13 MiniKansÔ, each containing one of the resin-bound
esters 46AeH [93 mequiv/MiniKanÔ prepared from 46.5 mg
of Merrifield resin with a loading of 2.0 mequiv (chloride)
4.4.6. N-Boc-2-(30-phenoxypropyl)-5-(400,500-tetramethyl-
100,300,200-dioxaborolan-200-yl)indole 48E
In the same way, one MiniKanÔ containing resin-bound
enol ether 47E (93 mequiv) gave indole 48E (17.5 mg, 42%).
dH (400 MHz, CDCl3): 1.36 (12H, s, CH3), 1.68 (9H, s,
tBu), 2.19 (2H, qn, J 7.4 Hz, CH2CH2CH2), 3.20 (2H, t,
J 7.2 Hz, CH2CH2CH2OPh), 4.04 (2H, t, J 7.4 Hz, CH2OPh),
6.37 (1H, s, H-3), 6.88e6.95 (3H, m, Ar-H), 7.27e7.29 (2H,
m, Ar-H), 7.67 (1H, dd, J 1.2 and 8.4 Hz, H-6), 7.92 (1H, d,
J 1.2 Hz, H-4), 8.07 (1H, d, J 8.4 Hz, H-7).
g
ꢀ1], that had been purged with argon were added. After
17 h the MiniKansÔ were removed from the flask and washed
with THF (5ꢂ) then alternately with MeOH and DCM (5ꢂ)
and finally with MeOH and Et2O. The 13 MiniKansÔ contain-
ing one of the resin-bound enol ethers 47AeH were then dried
under vacuum. The same procedure was employed for all eight
resin-bound esters 46AeH, using 104 MiniKansÔ in total.
4.4.7. N-Boc-2-[20-(300,400-dimethoxyphenyl)ethyl]-5-
(4000,5000-tetramethyl-1000,3000,2000-dioxaborolan-2000-yl)indole
48F
In the same way, one MiniKanÔ containing resin-bound
enol ether 47F (93 mequiv) gave indole 48F (27.1 mg, 58%).
dH (400 MHz, CDCl3): 1.36 (12H, s, CH3), 1.67 (9H, s,
tBu), 2.96 (2H, t, J 7.2 Hz, H-20), 3.30 (2H, t, J 7.4 Hz,
H-10), 3.81 (3H, s, OCH3), 3.86 (3H, s, OCH3), 6.32 (1H, s,
H-3), 6.71 (1H, d, J 1.6 Hz, H-200), 6.77e6.78 (2H, m, H-500
and H-600), 7.68 (1H, dd, J 1.2 and 8.4 Hz, H-6), 7.92 (1H,
d, J 1.2 Hz, H-4), 8.06 (1H, d, J 8.4 Hz, H-7).
4.4.2. N-Boc-2-(20-phenylethyl)-5-(400,500-tetramethyl-
100,300,200-dioxaborolan-200-yl)indole 48A
One MiniKanÔ containing resin-bound enol ether 47A
(93 mequiv) was shaken with trifluoroacetic acid (1%) in
DCM (5 mL) for 1.5 h. The solution was removed and the re-
actor was washed with DCM (3ꢂ). Combined organics were
concentrated under reduced pressure to give indole 47A
(23.7 mg, 57%). 1H NMR data as reported for indole 39 above.
4.4.8. N-Boc-2-[20-(piperidin-400-yl)ethyl]-5-(4000,500-
tetramethyl-1000,3000,2000-dioxaborolan-2000-yl)indole,
trifluoroacetate salt 48G0
4.4.3. N-Boc-2-propyl-5-(40,50-tetramethyl-10,30,20-
dioxaborolan-20-yl)indole 48B
In the same way, one MiniKanÔ containing resin-bound
enol ether 47E (93 mequiv) gave indole 48G0 (36.6 mg,
73%). dH (400 MHz, CDCl3): 1.37 (12H, s, CH3), 1.53e1.56
In the same way, one MiniKanÔ containing resin-bound
enol ether 47B (93 mequiv) gave indole 48B (21.8 mg, 61%).
dH (400 MHz, CDCl3): 1.03 (2H, t, J 7.2 Hz, CH3CH2), 1.37
(12H, s, CH3), 1.67 (9H, s, tBu), 2.93e2.98 (4H, m,
CH2CH2), 6.34 (1H, s, H-3), 7.65 (1H, dd, J 1.2 and 8.4 Hz,
H-6), 8.06 (1H, d, J 1.2 Hz, H-4), 8.21 (1H, d, J 8.4 Hz, H-7).
t
(5H, m, H-pip), 1.69 (9H, s, Bu), 2.00e2.10 (2H, m, piperi-
dine), 2.90e3.10 (4H, m, CH2CH2), 3.45e3.60 (2H, m, 2ꢂ
CHAHBN), 6.34 (1H, s, H-3), 7.68 (1H, dd, J 1.2 and
8.4 Hz, H-6), 7.93 (1H, s, H-4), 8.01 (1H, d, J 8.4 Hz, H-7),
9.11 (2H, br s, NH2).

912
C.A. Main et al. / Tetrahedron 64 (2008) 901e914
4.5. Indoles 49AaeHl
4.5.3. N-Boc-5-(30-cyanophenyl)-2-(200-phenylethyl)indole
49Ae
t
Pd(PPh3)4 (15 mg, 4 mol %) was added to a flask contain-
ing eight MiniKansÔ each containing a different resin-bound
enol ether 47AeH (93 mequiv/MiniKanÔ), stirring with
Cs2CO3 (1.21 g, 3.7 mmol), one of the aryl iodides aeh
(3.7 mmol) and water (13.3 mL, 0.74 mmol) in degassed
DMF (30 mL) under argon. The suspension was shaken at
80 ꢁC for 6 h. The mixture was allowed to cool and the Mini-
KansÔ were separated from the reaction mixture and washed
with 9:1 DMFeH2O (3ꢂ), alternately with MeOH and DCM
(3ꢂ) and finally with MeOH and Et2O. The MiniKansÔ con-
taining resin were then dried under vacuum. This procedure
was used for each of the 12 different aryl iodides aeh and
the resulting 96 MiniKansÔ, each containing a different
resin-bound enol ether, were placed in an IRORI ClevapÔ (au-
tomatic cleavage and evaporation) station, so that each Mini-
KanÔ was treated separately with trifluoroacetic acid (1%)
in DCM for 1.5 h, then with DCMeMeOH (4:1) for 0.5 h
and the combined organics from each MiniKanÔ were col-
lected separately and evaporated to give indoles 49AaeHl in
the yields and purities shown in Table 1. Analysis of the li-
brary was by reversed phase HPLC/DAD-UV/ELSD/MS using
a Waters Analytical 4-way MUX QC System with an Agilent
Zorbax SB C8, 21.2ꢂ250 mm column and eluting with 0.1%
dH (400 MHz, CDCl3): 1.71 (9H, s, Bu), 3.05 (2H, t,
J 7.8 Hz, CH2Ph), 3.37 (2H, t, J 7.8 Hz, CH2CH2Ph), 6.41
(1H, s, H-3), 7.18e7.32 (5H, m, Ph), 7.44 (1H, dd, J 2.0
and 8.8 Hz, H-6), 7.53 (1H, dt, J 0.4 and 7.6 Hz, H-50),
7.59e7.63 (2H, m, H-4 and H-60), 7.86 (1H, ddd, J 1.2, 2.0
and 8.0 Hz, H-40), 7.91e7.92 (1H, m, H-20), 8.16 (1H, d,
J 8.8 Hz, H-7).
4.5.4. N-Boc-5-(40-methoxyphenyl)-2-(300-phenyl-
propyl)indole 49Cb
t
dH (400 MHz, CDCl3): 1.68 (9H, s, Bu), 2.00e2.10 (2H,
m, CH2CH2CH2), 2.75 (2H, t, J 7.6 Hz, CH2Ph), 3.06 (2H, t,
J 7.6 Hz, CH2CH2CH2Ph), 3.85 (3H, s, OCH3), 6.39 (1H, s,
H-3), 6.98 (2H, d, J 8.8 Hz, H-30 and H-50), 7.17e7.32 (5H,
m, Ph), 7.42 (1H, dd, J 2.0 and 8.4 Hz, H-6), 7.56 (2H, d, J
8.8 Hz, H-20 and H-60), 7.60 (1H, d, J 1.6 Hz, H-4), 8.11
(1H, d, J 8.4 Hz, H-7).
4.5.5. N-Boc-5-(40-methoxyphenyl)-2-(300-phenoxy-
propyl)indole 49Eb
t
dH (400 MHz, CDCl3): 1.70 (9H, s, Bu), 2.21 (2H, tt,
J 6.4 and 7.4 Hz, CH2CH2CH2), 3.23 (2H, t, J 7.4 Hz,
CH2CH2CH2OPh), 3.85 (3H, s, OCH3), 4.06 (2H, t,
J 6.4 Hz, CH2OPh), 6.42 (1H, s, H-3), 6.89e6.98 (3H, m,
Ph), 7.00 (2H, d, J 2.8 Hz, H-30 and H-50), 7.26e7.30 (2H,
m, Ph), 7.43 (1H, dd, J 2.0 and 8.4 Hz, H-6), 7.54 (2H, d,
J 8.8 Hz, H-20 and H-60), 7.60 (1H, d, J 2.0 Hz, H-4), 8.10
(1H, d, J 8.4 Hz, H-7).
trifluoroacetic acid in MeCNeH2O (4:1), flow¼25 mL minꢀ1
.
HPLC MS data is displayed in Table 2 (library members in
1
bold also have H NMR data for the reversed phase HPLC-
purified indoles as listed below).
4.5.1. N-Boc-5-(40-methoxyphenyl)-2-(200-phenylethyl)indole
49Ab
Data are as reported under indole 41 above.
4.5.6. N-Boc-5-(20-methylphenyl)-2-(300-phenoxy-
propyl)indole 49Ec
4.5.2. N-Boc-5-(20-methylphenyl)-2-(200-phenylethyl)indole
49Ac
dH (400 MHz, CDCl3): 1.70 (9H, s, tBu), 2.28 (3H, s, CH3),
3.04 (2H, t, J 7.6 Hz, CH2Ph), 3.36 (2H, t, J 7.6 Hz,
CH2CH2Ph), 6.39 (1H, s, H-3), 7.20 (1H, dd, J 2.0 and
8.8 Hz, H-6), 7.22e7.32 (9H, m, Ph, H-30 to H-60), 7.38
(1H, d, J 2.0 Hz, H-4), 8.09 (1H, d, J 8.8 Hz, H-7).
dH (400 MHz, CDCl3): 1.70 (9H, s, tBu), 2.22 (2H, tt, J 6.2
and 7.4 Hz, CH2CH2CH2), 2.28 (3H, s, CH3), 3.24 (2H, t,
J 7.4 Hz, CH2CH2CH2OPh), 4.07 (2H, t, J 6.2 Hz, CH2OPh),
6.41 (1H, s, H-3), 6.90e6.96 (3H, m, Ph), 7.20 (1H, dd, J 2.0
and 8.4 Hz, H-6), 7.22e7.26 (6H, m, H-30 to H-60 and Ph),
7.37 (1H, d, J 2.0 Hz, H-4), 8.10 (1H, d, J 8.4 Hz, H-7).
Table 2
HPLC retention times (min) for indoles 49 (detected MþHþ in parenthesis)
A
B
C
D
E
F
G
H
a
a
b
c
d
e
f
1.73 (440.2)
5.30 (427.2)
1.61 (378.2)
4.75 (365.2)
6.41 (349.2)
1.88 (454.2)
1.44 (441.2)
1.42 (428.2)
1.58 (412.2)
1.40 (404.2)
1.35 (423.2)
1.73 (470.2)
5.33 (457.3)
7.23 (441.2)
5.14 (433.2)
4.92 (452.2)
5.99 (443.2)
3.83 (417.2)
4.40 (452.2)
3.92 (434.2)
9.12 (429.2)
1.53 (442.2)
5.22 (429.2)
1.49 (550.3)
3.93 (487.2)
5.17 (471.2)
3.79 (463.2)
3.66 (482.2)
4.19 (463.2)
1.52 (447.2)
3.35 (482.2)
2.98 (464.1)
6.17 (459.2)
1.37 (472.2)
3.84 (459.2)
2.00 (547.3)
7.46 (534.3)
a
6.32 (441.2)
8.72 (425.2)
6.03 (417.2)
5.87 (436.2)
6.78 (417.1)
a
7.22 (411.2)
a
5.24 (518.3)
a
a
a
a
4.90 (422.2)
5.64 (403.1)
1.26 (387.1)
4.34 (422.1)
3.89 (404.1)
8.57 (399.2)
1.51 (412.2)
5.10 (399.2)
4.43 (360.2)
1.44 (341.1)
6.86 (529.3)
8.02 (510.3)
2.06 (494.3)
a
1.45 (404.2)
a
a
a
a
g
h
i
3.93 (360.1)
3.46 (342.1)
7.55 (337.2)
1.44 (350.2)
4.50 (337.2)
5.15 (436.2)
4.59 (418.2)
1.33 (423.2)
1.26 (405.1)
1.49 (400.1)
1.28 (413.2)
1.30 (400.2)
5.92 (529.3)
a
1.45 (491.2)
1.48 (473.2)
a
j
11.52 (413.2)
4.97 (426.2)
6.36 (413.2)
5.33 (506.3)
1.72 (519.3)
7.81 (506.3)
a
a
k
l
a
MW of product not detected.

C.A. Main et al. / Tetrahedron 64 (2008) 901e914
913
4.5.7. N-Boc-5-(30-cyanophenyl)-2-(300-phenoxy-
propyl)indole 49Ee
J 1.6 Hz, H-2000), 6.74e6.82 (2H, m, H-5000 and H-6000), 7.45
(1H, dd, J 2.0 and 8.4 Hz, H-6), 7.52 (1H, dt, J 0.4 and
7.8 Hz, H-50), 7.59e7.63 (2H, m, H-4 and H-60), 7.86 (1H,
td, J 1.6 and 8.0 Hz, H-40), 7.91 (t, J 1.4 Hz, H-20), 8.17
(1H, d, J 8.8 Hz, H-7).
t
dH (400 MHz, CDCl3): 1.71 (9H, s, Bu), 2.22 (2H, tt,
J 6.2 and 7.4 Hz, CH2CH2CH2), 3.23 (2H, t, J 7.4 Hz,
CH2CH2CH2OPh), 4.06 (2H, t, J 6.2 Hz, CH2OPh), 6.44
(1H, s, H-3), 6.89e6.96 (3H, m, Ph), 7.26e7.31 (2H, m,
Ph), 7.43 (1H, dd, J 2.0 and 8.8 Hz, H-6), 7.53 (1H, t,
J 7.6 Hz, H-50), 7.59e7.63 (2H, m, H-4 and H-60), 7.86 (1H,
td, J 1.4 and 7.6 Hz, H-40), 7.91 (1H, t, J 1.6 Hz, H-20), 8.17
(1H, d, J 8.8 Hz, H-7).
4.5.13. N-Boc-5-(20-cyanophenyl)-2-[200-(3000,4000-
dimethoxyphenyl)ethyl]indole 49Fh
t
dH (400 MHz, CDCl3): 1.71 (9H, s, Bu), 2.98 (2H, t,
J 7.8 Hz, H-200), 3.34 (2H, t, J 7.8 Hz, H-100), 3.83 (3H, s,
OCH3), 3.86 (3H, s, OCH3), 6.42 (1H, s, H-3), 6.72e6.82
(3H, m, H-2000, H-5000 and H-6000), 7.40e7.45 (2H, m, H-40
and H-6), 7.55 (1H, dd, J 0.8 and 7.6 Hz, H-60), 7.62e7.66
(2H, m, H-4 and H-50), 7.77 (1H, dd, J 0.8 and 7.6 Hz,
H-30), 8.18 (1H, d, J 8.4 Hz, H-7).
4.5.8. N-Boc-5-(20-cyanophenyl)-2-(300-phenoxy-
propyl)indole 49Eh
t
dH (400 MHz, CDCl3): 1.70 (9H, s, Bu), 2.22 (2H, tt,
J 6.2 and 7.4 Hz, CH2CH2CH2), 3.24 (2H, t, J 7.4 Hz,
CH2CH2CH2), 4.06 (2H, t, J 6.2 Hz, CH2CH2OPh), 6.45
(1H, s, H-3), 6.88e6.96 (3H, m, Ph), 7.26e7.31 (2H, m,
Ph), 7.40e7.44 (2H, m, H-40 and H-6), 7.55 (1H, dd, J 0.8
and 7.6 Hz, H-60), 7.61e7.66 (2H, m, H-4 and H-50), 7.77
(1H, dd, J 2.0 and 8.0 Hz, H-30), 8.18 (1H, d, J 8.8 Hz, H-7).
4.5.14. N-Boc-2-[20-(N-Boc-piperidin-400-yl)ethyl]-5-(4000-
methoxyphenyl)indole 49Gb
dH (400 MHz, CDCl3): 1.06e1.25 (2H, m, piperidine), 1.46
(9H, s, tBu), 1.49e1.78 (5H, m, piperidine), 1.70 (9H, s, tBu),
2.60e2.70 (2H, m, CH2CH2CH), 3.05 (2H, t, J 7.6 Hz, H-10),
3.86 (3H, s, OCH3), 4.05e4.20 (2H, m, 2ꢂCHAHBN), 6.37
(1H, s, H-3), 6.99 (2H, d, J 8.8 Hz, H-3000 and H-5000), 7.43
(1H, dd, J 2.0 and 8.8 Hz, H-6), 7.55 (2H, d, J 8.8 Hz, H-2000
and H-6000), 7.58 (1H, d, J 2.0 Hz, H-4), 8.08 (1H, d,
J 8.8 Hz, H-7).
4.5.9. N-Boc-2-(30-phenoxypropyl)-5-(pyrazin-200-yl)indole
49El
t
dH (400 MHz, CDCl3): 1.71 (9H, s, Bu), 2.22 (2H, tt,
J 6.2 and 7.4 Hz, CH2CH2CH2), 3.24 (2H, t, J 7.4 Hz,
CH2CH2CH2), 4.07 (2H, t, J 6.2 Hz, CH2CH2OPh), 6.48
(1H, s, H-3), 6.89e6.97 (3H, m, Ph), 7.26e7.30 (2H, m,
Ph), 7.90 (1H, dd, J 1.6 and 8.8 Hz, H-6), 8.12 (1H, d,
J 1.6 Hz, H-4), 8.21 (1H, d, J 8.8 Hz, H-7), 8.47 (1H, d,
J 2.4 Hz, H-600), 8.62 (1H, dd, J 1.6 and 2.4 Hz, H-500), 9.08
(1H, d, J 1.6 Hz, H-300).
Acknowledgements
GSK and University of Glasgow for funding. Thanks to Ian
Davidson for HPLC-UV/MS.
4.5.10. N-Boc-2-[20-(300,400-dimethoxyphenyl)ethyl]-5-(4000-
methoxyphenyl)indole 49Fb
References and notes
t
dH (400 MHz, CDCl3): 1.70 (9H, s, Bu), 2.97 (2H, t,
J 7.8 Hz, CH2Ph), 3.33 (2H, t, J 7.8 Hz, CH2CH2Ph), 3.82
(3H, s, OCH3), 3.85 (3H, s, OCH3), 3.86 (3H, s, OCH3),
6.37 (1H, s, H-3), 6.73 (1H, d, J 1.6 Hz, H-200), 6.77e6.80
(2H, m, H-500 and H-600), 6.98 (2H, d, J 8.8 Hz, H-3000 and H-
5000), 7.44 (1H, dd, J 2.0 and 8.8 Hz, H-6), 7.55e7.60 (3H,
m, H-4, H-2000 and H-6000), 8.10 (1H, d, J 8.8 Hz, H-7).
1. Dolle, R. E.; Le Bourdonnec, B.; Morales, G. A.; Moriarty, K. J.; Salvino,
J. M. J. Comb. Chem. 2006, 8, 597e635.
2. Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger,
R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson, P. S.; Chang,
R. S. L.; Lotti, V. J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.; Kunkel, K. A.;
Springer, J. P.; Hirshfield, J. J. Med. Chem. 1988, 31, 2235e2246.
3. (a) Tan, D. S. Nat. Chem. Biol. 2005, 1, 74e84; (b) Prabhat, A.; Joseph,
R.; Gan, Z.; Rakic, B. Chem. Biol. 2005, 12, 163e180.
4. Reader, J. C. Curr. Top. Med. Chem. 2004, 4, 671e686.
5. For reviews see: (a) Hartley, R. C.; Li, J.; Main, C. A.; McKiernan, G. J.
Tetrahedron 2007, 63, 4825e4864; (b) Hartley, R. C.; McKiernan, G. J.
J. Chem. Soc., Perkin Trans. 1 2002, 2763e2793.
4.5.11. N-Boc-2-[20-(300,400-dimethoxyphenyl)ethyl]-5-(2000-
methylphenyl)indole 49Fc
t
dH (400 MHz, CDCl3): 1.70 (9H, s, Bu), 2.29 (3H, s,
ArCH3), 2.98 (2H, t, J 7.8 Hz, H-20), 3.33 (2H, t, J 7.8 Hz,
H-10), 3.82 (3H, s, OCH3), 3.87 (3H, s, OCH3), 6.37 (1H, s,
H-3), 6.73 (1H, s, H-200), 6.81 (2H, s, H-500 and H-600, coinci-
dent), 7.20 (1H, dd, J 2.0 and 8.8 Hz, H-6), 7.23e7.28 (4H, m,
H-3000 to H-6000), 7.37 (1H, d, J 2.0 Hz, H-4), 8.09 (1H, d,
J 8.8 Hz, H-7).
6. Guthrie, E. J.; Macritchie, J.; Hartley, R. C. Tetrahedron Lett. 2000, 41,
4987e4990.
7. Macleod, C.; McKiernan, G. J.; Guthrie, E. J.; Farrugia, L. J.; Hamprecht,
D. W.; Macritchie, J.; Hartley, R. C. J. Org. Chem. 2003, 68, 387e401.
8. Roberts, C. F.; Hartley, R. C. J. Org. Chem. 2004, 69, 6145e6148.
9. Macleod, C.; Austin, C. A.; Hamprecht, D. W.; Hartley, R. C. Tetrahedron
Lett. 2004, 45, 8879e8882.
10. Austin, C.; Smith, D.; Hartley, R. C. J. Labelled Compd. Radiopharm.
2007, 50, 502e503.
11. Adriaenssens, L. V.; Austin, C. A.; Gibson, M.; Smith, D.; Hartley, R. C.
Eur. J. Org. Chem. 2006, 4998e5001.
4.5.12. N-Boc-5-(30-cyanophenyl)-2-[200-(3000,4000-
dimethoxyphenyl)ethyl]indole 49Fe
dH (400 MHz, CDCl3): 1.71 (9H, s, Bu), 2.98 (2H, t,
t
12. Ball, C. P.; Barrett, A. G. M.; Commerc¸on, A.; Compere, D.; Kuhn, C.;
Roberts, R. S.; Smith, M. L.; Venier, O. Chem. Commun. 1998, 2019e
2020.
J 7.6 Hz, H-200), 3.34 (2H, t, J 7.6 Hz, H-100), 3.82 (3H, s,
OCH3), 3.86 (3H, s, OCH3), 6.33 (1H, s, H-3), 6.73 (1H, d,

914
C.A. Main et al. / Tetrahedron 64 (2008) 901e914
13. Barrett, A. G. M.; Procopiou, P. A.; Voigtmann, U. Org. Lett. 2001, 3,
3165e3168.
25. Horikawa, Y.; Watanabe, M.; Fujiwara, T.; Takeda, T. J. Am. Chem. Soc.
1997, 119, 1127e1128.
14. McKiernan, G. J.; Hartley, R. C. Org. Lett. 2003, 5, 4389e4392.
15. Kasahara, T.; Kondo, Y. Heterocycles 2006, 67, 95e100.
16. Review: Somei, M.; Yamada, F. Nat. Prod. Rep. 2005, 22, 73e103.
26. Similar boronates are useful synthetic intermediates: (a) Stadlwieser, J. F.;
Dambaur, M. E. Helv. Chim. Acta 2006, 89, 936e946; (b) Prieto, M.;
Zurita, E.; Rosa, E.; Munoz, L.; Lloyd-Williams, P.; Giralt, E. J. Org.
Chem. 2004, 69, 6812e6820; (c) Okada, M.; Sato, I.; Cho, S. J.; Suzuki,
Y.; Ojika, Ma.; Dubnau, D.; Sakagami, Y. Biosci. Biotechnol. Biochem.
2004, 68, 2374e2387; (d) Song, Y.-L.; Morin, C. Synlett 2001, 266e268.
27. Recent examples include: (a) Miki, Y.; Aoki, Y.; Miyatake, H.; Mine-
matsu, T.; Hibino, H. Tetrahedron Lett. 2006, 47, 5215e5218; (b) Trost,
B. M.; Quancard, J. J. Am. Chem. Soc. 2006, 128, 6314e6315; (c) Rawat,
M.; Wulff, W. D. Org. Lett. 2004, 6, 329e332.
´
17. Review: Holenz, J.; Pauwels, P. J.; Dıaz, J. L.; Marce, R.; Codony, X.;
`
Buschmann, H. Drug Discov. Today 2006, 11, 283e299.
18. (a) Riggs, J. R.; Kolesnikov, A.; Hendrix, J.; Young, W. B.; Shrader,
W. D.; Vijaykumar, D.; Stephens, R.; Liu, L.; Pan, L.; Mordenti, J.; Green,
M. J.; Sukbuntherng, J. Bioorg. Med. Chem. Lett. 2006, 16, 2224e2228;
(b) Kolesnikov, A.; Rai, R.; Young, W. B.; Mordenti, J.; Liu, L.; Torkel-
son, S.; Shrader, W. D.; Leahy, E. M.; Hu, H.; Gjerstad, E.; Janc, J.;
Katz, B. A.; Sprengeler, P. A. Bioorg. Med. Chem. Lett. 2006, 16,
2243e2246.
28. Recent examples include: (a) Yamabuki, A.; Fujinawa, H.; Choshi, T.;
Tohyama, S.; Matsumoto, K.; Ohmura, K.; Nobuhiro, J.; Hibino, S.
´
Tetrahedron Lett. 2006, 47, 5859e5861; (b) Belanger, G.; Larouche-
19. (a) Sugimoto, Y.; Shimizu, A.; Kato, T.; Satoh, A.; Ozaki, S.; Ohta, H.;
Okamoto, O. Bioorg. Med. Chem. Lett. 2006, 16, 3569e3573; (b) Koppitz,
M.; Reinhardt, G.; van Lingen, A. Tetrahedron Lett. 2005, 46, 911e914.
20. Payack, J. F.; Vazquez, E.; Matty, L.; Kress, M. H.; McNamara, J. J. Org.
Chem. 2005, 70, 175e178.
´
´
Gauthier, R.; Menard, F.; Nantel, M.; Barabe, F. J. Org. Chem. 2006,
71, 704e712; (c) Pelly, S. C.; Parkinson, C. J.; van Otterlo, W. A. L.;
de Koning, C. B. J. Org. Chem. 2005, 70, 10474e10481; (d) Baran,
P. S.; Shenvi, R. A.; Mitsos, C. A. Angew. Chem., Int. Ed. 2005, 44,
3714e3717.
21. Brands, M.; Erguden, J.-K.; Hashimoto, K.; Heimbach, D.; Schroder, C.;
¨
¨
Siegel, S.; Stasch, J.-P.; Weigand, S. Bioorg. Med. Chem. Lett. 2005, 15,
4201e4205.
29. Miyaura coupling is reported to be effective for aldehyde 16: DiMauro,
E. F.; Vitullo, J. R. J. Org. Chem. 2006, 71, 3959e3962.
30. Zhu, L.; Duquette, J.; Zhang, M. J. Org. Chem. 2003, 68, 3729e3732.
31. Clayden, J. Organolithiums: Selectivity for Synthesis; Pergamon: London,
2002; Chapter 3.
´
22. Reviews: (a) Tois, J.; Franzen, R.; Koskinen, A. Tetrahedron 2003, 59,
5395e5405; (b) Brase, S.; Gil, C.; Knepper, K. Bioorg. Med. Chem.
¨
2002, 10, 2415e2437.
23. Recent examples involving construction of the indole moiety include: (a)
Yao, T.; Yue, D.; Larock, R. C. J. Comb. Chem. 2005, 7, 809e812; (b)
32. Sieh, D. H.; Wilbur, D. J.; Michejda, C. J. J. Am. Chem. Soc. 1980, 102,
3883e3887.
Rosenbaum, C.; Rohrs, S.; Muller, O.; Waldmann, H. J. Med. Chem.
33. (a) Isaacs, N. S.; Rannala, E. J. Chem. Soc., Perkin Trans. 2 1974, 899e
902; (b) Smith, R. H., Jr.; Denlinger, C. L.; Kupper, R.; Mehl, A. F.;
Michejda, C. J. J. Am. Chem. Soc. 1986, 108, 3726e3730; (c)
Farnsworth, D. W.; Wink, D. A.; Roscher, N. M.; Michejda, C. J.;
Smith, R. H., Jr. J. Org. Chem. 1994, 59, 5942e5950.
¨
¨
2005, 48, 1179e1187; (c) Mun, H.-S.; Ham, W. H.; Jeong, J.-H.
J. Comb. Chem. 2005, 7, 130e135; (d) Ohno, H.; Tanaka, H.; Takahashi,
T. Synlett 2004, 508e511; (e) Yamazaki, K.; Nakamura, Y.; Kondo, Y.
J. Org. Chem. 2003, 68, 6011e6019; (f) Rosenbaum, C.; Katzka, C.;
Marzinzik, A.; Waldmann, H. Chem. Commun. 2003, 1822e1823; (g)
Wu, Z.; Ede, N. J. Org. Lett. 2003, 5, 2935e2938; (h) Dai, W.-M.;
Guo, D.-S.; Sun, L.-P.; Huang, X.-H. Org. Lett. 2003, 5, 2919e2922; (i)
34. Brase, S. Acc. Chem. Res. 2004, 37, 805e816.
¨
35. Kabalka, G. W.; Li, G. Tetrahedron Lett. 1997, 38, 5777e5778.
36. Clark, R. D.; Muchowski, J. M.; Fisher, L. E.; Flippin, L. A.; Repke,
D. B.; Souchet, M. Synthesis 1991, 871e878.
Knepper, K.; Brase, S. Org. Lett. 2003, 5, 2829e2832; (j) Lee, S.-H.;
¨
Clapham, B.; Koch, G.; Zimmermann, J.; Janda, K. D. J. Comb. Chem.
2003, 5, 188e196; (k) Tanaka, H.; Ohno, H.; Kawamura, K.; Ohtake,
A.; Nagase, H.; Takahashi, T. Org. Lett. 2003, 5, 1159e1162.
24. Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508e
7510.
37. For a review see: Schlummer, B.; Scholz, U. Adv. Synth. Catal. 2004, 346,
1599e1626.
38. A related copper-catalysed process is known: Klapars, A.; Antilla, J. C.;
Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7727e7729.
39. Balle, T.; Andersen, K.; Vedsø, P. Synthesis 2002, 1509e1512.