Traceless solid-phase synthesis of 5-benzoylbenzimidazoles

Article abstract of DOI:10.1139/v01-138

A traceless linker strategy for the solid-supported synthesis of 5-benzoylbenzimidazoles has been developed. A benzyl cyanide functional group was linked to 2% divinylbenzene cross-linked polystyrene through a dimethylsilyl linker. Coupling with 5-chloro-

Full text of DOI:10.1139/v01-138

1556
Traceless solid-phase synthesis of
5-benzoylbenzimidazoles
Kyung Joo Lee and Kim D. Janda
Abstract: A traceless linker strategy for the solid-supported synthesis of 5-benzoylbenzimidazoles has been developed.
A benzyl cyanide functional group was linked to 2% divinylbenzene cross-linked polystyrene through a dimethylsilyl
linker. Coupling with 5-chloro-2-nitroaniline followed by oxidative decyanation gave benzophenone 11 as a key intermediate
in an efficient one-pot reaction procedure. After reduction of the nitro group and oxidative cyclization with a variety of
aldehydes in the presence of DDQ, a series of polymer-supported benzimidazoles was produced. Final traceless cleavage
of the arylsilane linker with TBAF provided a small library of 5-benzoylbenzimidazoles.
Key words: solid-support, traceless linker, arylsilane, 5-benzoylbenzimidazole.
Résumé : On a développé une stratégie d’ancrage sans trace pour la synthèse sur support solide de 5-benzoylbenzimidazoles.
Utilisant un diméthylsilyle comme ancre, on a relié un cyanure de benzyle fonctionnalisé à du polystyrène réticulé à
2% de divinylbenzène. Son couplage avec de la 5-chloro-2-nitroaniline, suivi d’une décyanation oxydante, conduit à la
benzophénone 11, un intermédiaire clé dans une réaction monotope efficace. Après réduction du groupe nitro et cyclisation
oxydante avec une variété d’aldéhydes, en présence de DDQ, on obtient une série de benzimidazoles supportés par un
polymère. Un clivage final sans laisser de trace de l’ancre arylsilane, par du TBAF, conduit à une série de 5-benzoy-
lbenzimidazoles.
Mots clés : support solide, ancre sans trace, arylsilane, 5-benzoylbenzimidazole.
[Traduit par la Rédaction] 1561
Introduction
Lee and Janda key element in the synthetic design. Indeed, major drawbacks
inherent to solid-phase synthesis are related to the linking of
the molecule to the support, the linker’s chemical inertness,
Benzimidazoles and in particular 2-substituted benzimidazoles
show a broad range of medicinal activity including fungicidal,
antitumor, and antiviral, with the antiulcerative Omeprazole
(1) and antihistamine Astemizole (2) being clinical examples.
In addition, benzimidazole-based compounds have been
found to be inhibitors of phosphodiesterase IV (3) and
antagonists of angiotensin I (4). Because of their medicinal
importance, the solid-phase synthesis of heterocycles such as
benzimidazoles, diketopiperazines, diazines, and hydantoins
that contain one or more nitrogen atoms has received consid-
erable attention. Consequently, a general method for the
rapid synthesis of a library of benzimidazoles might provide
new lead compounds in drug discovery based efforts.
Our efforts in the library preparation of benzimidazoles
were centered upon structures such as 1, 2-substituted-5-
benzoylbenzimidazole. We envisioned that this benz-
imidazole and the related supported intermediate 12 could
be utilized as precursors to a range of medicinally important
molecules such as Enviroxime, Enviradene, and Itemazole
(5). In accessing such structures via a solid-supported
methodology, linking group strategies must be considered a
and ease of detachment of the final molecule. A further
consideration is the potential remains of the linking func-
tionality. Thus, carboxyl, carboxamide, amine, or hydroxyl
functionalities are often left embedded within the target
molecule as a result of the linking strategies engaged.
Clearly, these moieties can affect the physico-chemical and
biological properties of the target molecule. Therefore, the
development of traceless linker strategies is an important
challenge in solid-phase combinatorial synthesis.
Recently, several novel tactics that utilize a resin-bound
arylsilane as a traceless linker have been successfully
applied to the solid-phase synthesis of aromatic and hetero-
aromatic compounds including 1,4-benzodiazepines (6),
benzofurans (7), tricyclics (8), and biaryl (9) structures. Fur-
thermore, a number of papers describing the solid or
soluble-polymer supported synthesis of benzimidazole deriv-
atives (10, 11) have also appeared. However, in these reports
of benzimidazoles, all the structures described show retained
linker functionality within the final compound. Herein, we
report the traceless solid-phase synthesis of 5-benzoyl-
benzimidazoles employing an arylsilane linkage.
Received February 13, 2001. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on October 24, 2001.
We dedicated this paper to our good friend Professor Victor Snieckus.
K.J. Lee and K.D. Janda.1 Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research
Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, U.S.A.
1Corresponding author (telephone: +1 858-784-2516; fax: +1 858-784-2595; e-mail: kdjanda@scripps.edu).
Can. J. Chem. 79: 1556–1561 (2001)
© 2001 NRC Canada
DOI: 10.1139/cjc-79-11-1556

Lee and Janda
1557
Scheme 1. Reagents and conditions: (a) n-BuLi, THF, –78°C, then allylchloro-dimethylsilane; (b) 9-BBN, THF, rt, 3.5 h, then 4-bro-
mopolystyrene, THF, Pd(PPh3)4, 2 M Na2CO3, 60°C, 72 h; (c) p-TsOH·H2O (0.1 equiv.), THF, H2O, rt; (d) Ph3P, CBr4, CH2Cl2, rt;
(e) NaCN, DMF–H2O, reflux, 1 h; (f) Br2, CH2Cl2, rt, 1 h.
Si
Si
Si
Br
c, d
a
b
5
OTBS
OTBS
Br
OTBS
4
3
2
e
a
Si
Si
Si
Si
e
b
c, d
CN
OTBS
CN
Br
8
3
6
7
f
Br
CN
with sodium cyanide in a DMF–water solvent system. The
loading level of 8 was determined to be 1.2 mmol g–1 by
mass balance of 4-bromobenzyl cyanide, which was
obtained from the electrophilic cleavage reaction of a small
aliquot of the resin with Br2. Alternatively, 8 could be
accessed if the hydroboration–Suzuki coupling protocol was
conducted at a later stage with preformed benzyl cyanide 7.
With intermediate 8 in hand, our 5-benzoylbenzimidazole
library synthesis was accomplished as shown in Scheme 2.
Results and discussion
We envisioned diamine 12 as the key intermediate in our
approach to 5-benzoylbenzimidazoles (see below). In solution
phase synthesis, this type of benzophenone can be prepared
readily from a Friedel-Crafts acylation reaction; however,
this strategy cannot be implemented in a polystyrene-based
system due to the presence of the aromatic backbone on the
resin. Alternatively, 12 could be prepared from an aldehyde
and organolithium or organomagnesium reagent followed by
oxidation of the resultant secondary alcohol; however, this
reaction sequence requires rigorous anhydrous conditions not
readily adaptable to a solid support and ultimately automation
of the process.
We thus envisioned that 11 could be prepared by oxidative
decyanation (12) of diaryl cyanide 9. It was our contention
that 9 could be obtained from the nucleophilic substitution
reaction of 5-chloro-2-nitroaniline with the anion of solid-
supported benzyl cyanide 8. This kind of oxidative
decyanation has been exemplified in the solution phase
synthesis of various benzophenone derivatives (5a).
Our route to solid-supported benzyl cyanide 8 is illustrated
in Scheme 1. Thus, 2 was lithiated and quenched with
chlorodimethylallylsilane to give the arylsilane derivative 3
that was attached subsequently to the polymer in a two step
procedure. Hydroboration of the allylsilane followed by in
situ Suzuki coupling (13) with bromophenylsubstituted resin
(1.97 mmol g–1) provided the silyl-derivatized resin 4.
Deprotection of the TBS group with acid followed by
bromination of the resultant alcohol gave the benzyl bromide
derivative 5. The key intermediate, polymer-supported
benzyl cyanide 8 was then obtained from the reaction of 5
Solid-supported benzyl cyanide 8 was treated with 5-chloro-
2-nitroaniline in the presence of an excess of potassium
tert-butoxide at room temperature. The requirement for
excess base (>2 equiv.) is essential to drive the first step
(nucleophilic aromatic substitution) of the reaction sequence
to completion due to the increased acidity of the a-hydrogen
found on the disubstituted nitrile product 9. Oxidation of 9
was performed in situ with 30% aqueous hydrogen peroxide
to afford the desired benzophenone derivative 11 after acidifi-
cation, so that the overall reaction sequence to give ketone
11 can be accomplished conveniently in a one-pot procedure.
To confirm the structure and to determine the loading value,
an aliquot of 11 was subjected to cleavage. Usually, the
aryl—silicon bond is cleaved by trifluoroacetic acid (i.e.,
protodesilylation). However, an aryl—silicon bond can be
quite stable if the aromatic ring possesses a strong electron-
withdrawing group within its nucleus. In this scenario the
ipso-substituted intermediate, needed to generate a carbonium
ion b to the silicon moiety is prevented. In such cases, fluoride
ion has proven to be an effective alternative (9–11, 14).
Thus, the benzophenone resin 11 was cleaved effectively
with tetrabutylammonium fluoride (TBAF) to give 5-
1
benzoyl-2-nitroaniline. This was confirmed by H NMR as
© 2001 NRC Canada

1558
Can. J. Chem. Vol. 79, 2001
Scheme 2. Reagents and conditions: (a) (i) 5-chloro-2-nitroaniline, t-BuOK, rt, 21 h, (ii) 30% H2O2, 0°C to rt, 22 h, (iii) 1 N HCl, rt,
15 min; (b) SnCl2·2H2O, DMF, 65°C, 27 h; (c) RCHO (5 equiv.), DDQ (2 equiv.), DMF, rt, 7 h; (d) 1 M TBAF, THF, 60°C, 24 h.
Si
Si
NO2
NH2
Si
NO2
NH2
[O]
a
CN
CN
CN
10
9
8
Si
NH2
NH2
Si
NO2
NH2
c
b
O
O
12
11
N
Si
N
d
R
R
N
H
N
H
O
O
1
13
well as high resolution mass spectrometry (HRMS) and a
loading value between 0.34~0.5 mmol g–1 was calculated for
11. Reduction of the polymer-supported nitroaniline 11 was
achieved by treatment with SnCl2 in DMF at 60°C (incom-
plete reduction was observed at room temperature even with
benzimidazoles. Furthermore, reduction of the carbonyl group
found in 13 and subsequent derivatization of the resultant alco-
hol would give 2,5-disubstitutedbenzimidazoles. Efforts
along these lines to construct more diversified libraries in
the pursuit of interesting biological active compounds are
currently in progress.
1
a prolonged reaction time), and was confirmed by H NMR
after cleavage of a small amount of the resin with TBAF.
Among the many procedures for the preparation of
benzimidazoles from diamines, 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone (DDQ) mediated oxidative cyclocondensation
with an aldehyde is attractive because of its mild reaction
conditions (6c, 6f, 15). Thus, treatment of resin 12 with an
aldehyde (5 equiv.) and DDQ (2 equiv.) in DMF at room
temperature gave the resin bound benzimidazole 13. Cleavage
from the support was accomplished by treatment with TBAF
in warm THF (60°C) to provide the desired 5-benzoyl-
benzimidazoles 1a–k (Table 1).
Experimental
General
Unless otherwise noted, materials were obtained from
commercial suppliers and used without further purification.
Tetrahydrofuran (THF) was distilled immediately before use
from sodium–benzophenone under N2. Anhydrous dimethy-
lformamide (DMF) was obtained from Aldrich in a SureSeal
bottle. All reactions were run under an inert atmosphere with
dry reagents and solvents and flame-dried glassware. Flash
column chromatography was carried out using Merck
60 230–400 mesh silica gel. Thin layer chromatography was
performed using 0.25 mm silica gel coated Kieselgel 60 F254
plates and visualized using aqueous cerium molybdate with
In general, the purities of the crude products as determined
1
by H NMR were greater than 85%. The isolated yields
(following purification over silica gel), calculated based on
the substitution level of the benzophenone resin 11, were
between 48 and 70%. The cyclocondensation–oxidation
reaction was efficient with electron-rich aromatic (1c, 1g),
electron-deficient aromatic (1b, 1d), heteroaromatic (1e, 1f),
and aliphatic (1h–k) aldehydes. All final compounds were
1
heating. H NMR and 13C NMR spectra were recorded on a
Bruker AMX-400 spectrometer at 400 and 100 MHz, respec-
tively, in CDCl3 or CD3OD at 25°C. Chemical shifts are
reported in ppm on the d scale from an internal TMS
standard. 4-Bromopolystyrene resin was purchased from
Novabiochem (San Diego, CA). Large scale solid-phase
reactions were performed in peptide-flasks with glass tubes
equipped for vacuum filtration (ChemGlass Inc., Vineland,
NJ) and were agitated with a Ika-Vibrax-Vxr shaker (Germany).
1
characterized by H NMR, 13C NMR, and HRMS.
In summary, we have developed a traceless linker strategy
for the solid-supported synthesis of 2-substituted-5-
benzoylbenzimidazoles 1. The key feature of our synthetic
strategy was the oxidative decyanation of 9 to give ketone 11
in an efficient one-pot procedure. It is anticipated that
resin-bound intermediates 12 and 13 could serve as scaffolds
for more diversified compound libraries. For example,
regiospecific acylation or sulfonylation of 12 and subsequent
O-tert-Butyldimethylsilyl-4-allyldimethylsilylbenzyl ether (3)
To a solution of tert-butyldimethylsilyl-4-bromobenzyl
ether (1, 14.4 g, 47.8 mmol) in dry THF (150 mL) at –78°C
was slowly added n-BuLi (29.9 mL, 1.6 M solution in hexane,
cyclization
would
give
1,2-disubstituted-5-benzoyl-
© 2001 NRC Canada

Lee and Janda
1559
Table 1.
Yield, %a
70
Entry
Aldehydes
Benzimidazoles
N
1a
CHO
N
H
O
N
64
52
NO
2
1b
1c
O N
2
CHO
CHO
N
H
O
N
OCH
3
H CO
3
N
H
O
N
60
Cl
Cl
CHO
N
H
1d
O
N
O
S
56
66
1e
1f
N
H
CHO
O
S
O
N
CHO
N
H
O
N
CHO
48
1g
N
H
OCH
3
H CO
3
O
N
CHO
56
68
1h
1i
N
H
O
N
CHO
N
H
O
CHO
N
61
66
1j
N
H
O
N
CHO
1k
N
H
O
a Isolated yields after purification by silica gel chromatography
47.8 mmol). After 20 min of further stirring at –78°C,
allylchlorodimethylsilane (6.98 mL, 47.8 mmol) was added
slowly and the reaction mixture was warmed to room
temperature. After 30 min, saturated NH4Cl (1 mL) was
added followed by sodium sulfate and the reaction mixture
was then filtered, concentrated, and purified by column chro-
matography (ethyl acetate–hexane, 1:20) to give a colorless
liquid (14.2 g, 93%). 1H NMR (CDCl3) d: 7.50 (d, J =
7.9 Hz, 2H), 7.36 (d, J = 7.9 Hz, 2H), 5.79 (m, 1H), 4.86
(m, 2H), 4.77 (s, 2H), 0.98 (s, 9H), 0.29 (s, 6H), 0.13 (s,
6H). 13C NMR (CDCl3) d: 142.3, 136.9, 134.7, 133.6, 125.4,
113.3, 64.9, 26.0, 23.8, 18.5, –3.4, –5.2.
© 2001 NRC Canada

1560
Can. J. Chem. Vol. 79, 2001
TBAF. Removal of CH2Cl2 under reduced pressure provided
5-benzoyl-2-nitroaniline (10 mg, 0.41 mmol) as a bright yellow
solid whose structure was confirmed by H NMR and mass
Preparation of 4
To a solution of 3 (3.0 g, 9.4 mmol) in dry THF (30 mL)
was added 9-BBN (18.7 mL, 0.5 M solution in THF) at
room temperature. After stirring for 3 h, Pd(PPh3)4 (324 mg,
3 mol%), a 2 M Na2CO3 solution (4.8 mL, 9.6 mmol), and
4-bromopolystyrene (3 g, 1.97 mmol g–1, 5.9 mmol) were
added and the reaction mixture was stirred gently at 65°C in
the dark. After 48 h, additional Pd(PPh3)4 (160 mg) was
added and the heating and stirring was continued for 24 h.
After a total of 72 h of heating, the mixture was allowed to
cool to room temperature. The resin was filtered and washed
with THF, THF–H2O (1:1), H2O, MeOH, DMF, MeOH, and
[CH2Cl2, MeOH]3 and then dried under vacuum to give
3.6 g of polymer.
1
spectrometry.
Preparation 12
To resin 11 (3.0 g, 1.23 mmol) in DMF (30 mL) was
added an excess of SnCl2·2H2O (4 g, 12.3 mmol) and the
mixture was stirred gently at 65°C. After 10 h, additional
SnCl2·2H2O (4 g) was added and the mixture was stirred for
a further 10 h. The reaction mixture was cooled to room
temperature and the resin was filtered, washed with DMF
several times, and dried under vacuum to provide a dark red
resin (2.9 g).
General procedure for the preparation of 5-benzoyl-
benzimidazoles (1)
Preparation of 8
To a mixture of resin 4 (3.6 g) in THF–water (20:1 mL)
was added a catalytic amount of p-TsOH·H2O (50 mg).
After shaking overnight at room temperature, the resin was
washed with THF, THF–H2O (1:1), H2O, MeOH, and
[CH2Cl2, MeOH]3 and then dried under vacuum. To a mixture
of this resin and Ph3P (1.4 g) in CH2Cl2 (40 mL) was slowly
added CBr4 (1.7 g). After shaking overnight at room temper-
ature, the resin was filtered and washed with THF, CH2Cl2,
MeOH, and [CH2Cl2, MeOH]3 and then dried under vacuum
to give polymer 5.
To the above resin 5 (3.5 g) swelled in DMF–H2O
(20:10 mL) was added an excess of sodium cyanide (2.0 g)
and the suspension was stirred gently at 80°C for 3 h. The
resin was filtered and washed with THF–H2O (1:1), H2O,
MeOH, THF, and [MeOH, CH2Cl2]3 and then dried under
vacuum to give polymer 8. To determine the loading level of
resin 8, 100 mg of the resin was swelled in 5 mL of CH2Cl2
and Br2 (30 L) was added. After stirring for 1 h at room
temperature, the resin was filtered and washed with CH2Cl2.
The combined filtrate was concentrated to give 4-
bromobenzylcyanide (23.4 mg, 1.2 mmol g–1), whose
identity was confirmed by 1H NMR and mass spectrometry.
To resin 12 (0.2 g, 0.08 mmol) in DMF (5 mL) was added
an aldehyde (5 equiv.) and DDQ (2 equiv.) and the mixture
was stirred gently for 7 h at room temperature. The resulting
resin was washed with CH2Cl2, DMF, and [CH2Cl2, MeOH]3
and dried under vacuum to provide the resin bound
benzimidazoles 13. The resin was cleaved with 1 M solution
of TBAF (2 mL) in THF at 65°C overnight and worked-up
as in the cleavage of resin 11 vide supra. The crude residue
was redissolved and purified by column chromatography
(CHCl3–MeOH, 20:1) to give 1a–k.
1a: Prepared from benzaldehyde, 70%. HRMS calcd. for
1
C20H15N2O: 299.1179; found: 299.1167. H NMR (CDCl3)
d: 8.17, (s, 1H), 8.10 (m, 2H), 7.84 (m, 3H), 7.58 (t, 1H).
1b: Prepared from 4-nitrobenzaldehyde, 64%. HRMS
calcd. for C20H12N3O3: 342.0884; found: 342.0888. 1H NMR
(DMSO-d6) d: 7.60 (s, 1H), 7.40 (m, 1H), 7.30 (m, 4H), 7.22
(m, 3H), 7.11 (m, 4H).
1c: Prepared from p-anisaldehyde, 52%. HRMS calcd. for
1
C21H17N2O2: 329.1285; found: 329.1282. H NMR (CDCl3)
d: 8.08 (m, 3H), 7.78 (m, 3H), 7.55 (m, 2H), 7.46 (m, 2H),
6.93 (d, J = 9.1 Hz, 2H), 3.82 (s, 3H). 13C NMR (CDCl3) d:
197.2, 161.6, 138.2, 132.1, 131.9, 130.0, 128.5, 128.2,
125.4, 121.7, 114.5, 55.4.
Preparation of 11
To a mixture of resin 8 (3.0 g, 3.6 mmol) and 5-chloro-2-
nitroaniline (2.4 g, 14.4 mmol) in anhydrous DMF (40 mL)
was added potassium tert-butoxide (2.4 g, 21.6 mmol) in
one portion at 0°C. The reaction mixture immediately turned
to an intense dark red color. The mixture was stirred gently
for 21 h at room temperature and then cooled to 0°C with an
ice bath. Hydrogen peroxide (7.5 mL, 30% solution) was
added and the mixture was stirred for 22 h at room temperature.
At this time, the color changed to dark green. After the
addition of 1 N HCl (45 mL) and stirring for 15 min, the
color of the mixture turned bright yellow. The resin was
washed thoroughly with THF, H2O (5 times), DMF, H2O,
[THF, MeOH]3, and [CH2Cl2, MeOH]3 to give yellow beads
(3.7 g). A portion of the above resin (100 mg) was treated
with a 1 M solution of TBAF (50 L) in THF at room
temperature overnight. The resin was filtered, rinsed with
THF and MeOH, and the combined filtrate was concentrated
to afford a residue that was subjected to extractive work up
with CH2Cl2–H2O. The residue obtained from concentration
of the CH2Cl2 layer was taken up in CH2Cl2 and further
extracted with water to remove a small amount of residual
1d: Prepared from 4-chlorobenzaldehyde, 60%. HRMS
calcd. for C20H13ClN2O: 333.0789; found: 333.0776. 1H
NMR (MeOH-d4) d: 7.98 (s, 1H), 7.96 (s, 1H), 7.95 (m,
1H), 7.73 (m, 1H), 7.66 (m, 3H), 7.52 (m, 3H), 7.43 (m,
3H). 13C NMR (MeOH-d4) d: 198.2, 154.4, 141.6, 139.4,
139.1, 138.5, 134.7, 133.8, 131.1, 130.9, 130.0, 129.7, 127.7,
127.3, 119.1, 115.7.
1e: Prepared from 2-furylaldehyde, 56%. HRMS calcd. for
C18H13N2O2: 289.0972; found: 289.0969. 1H NMR (MeOH-
d4) d: 7.91 (s, 1H), 7.67 (m, 4H), 7.54 (m, 2H), 7.43 (m,
2H), 7.18 (d, J = 2.96 Hz, 1H), 6.61 (m, 1H). 13C NMR
(MeOH-d4) d: 198.6, 146.7, 146.1, 139.8, 133.7, 133.6, 131.1,
129.6, 126.6, 113.6, 113.3.
1f: Prepared form 2-thiophenecarboxaldehyde, 66%. HRMS
calcd. for C18H13N2OS: 305.0743; found: 305.0747. 1H
NMR (MeOH-d4) d: 7.89 (m, 1H), 7.77 (m, 2H), 7.66 (m,
2H), 7.59 (m, 1H), 7.54 (m, 2H), 7.43 (m, 2H), 7.12 (dd, J =
© 2001 NRC Canada

Lee and Janda
1561
5.0, 3.5 Hz, 1H). 13C NMR (MeOH-d4) d: 197.5, 138.6,
132.4, 132.3, 129.9, 129.7, 128.5, 128.4, 128.3, 128.1.
Institute, and the National Institute of Health (GM 56154).
We thank Thomas S. Reger for proofreading of the manuscript.
1g: Prepared from 5-methoxynaphthaldehyde, 48%. HRMS
calcd. for C25H19N2O2: 379.1441; found: 379.1449. 1H
NMR (MeOH-d4) d: 8.34 (s, 1H), 7.99 (dd, J = 7.0, 1.5 Hz,
1H), 7.92 (s, 1H), 7.75 (m, 2H), 7.65 (m, 3H), 7.55 (m, 2H),
7.43 (t, J = 6.2 Hz, 2H), 7.15 (d, J = 2.1 Hz, 1H), 7.07 (dd, J =
7.2, 2.0 Hz, 1H). 13C NMR (MeOH-d4) d: 197.5, 138.7,
136.4, 132.4, 132.2, 130.2, 129.9, 128.9, 128.4, 127.9, 126.8,
125.2, 124.2, 124.1, 119.9, 54.9.
References
1. J.E. Richter. Am. J. Gastroenterol. 92, 34 (1997).
2. H.J. Al-Muhaimeed. Int. Med. Res. 25, 175 (1997).
3. J.B. Cheng, K. Cooper, A.J. Duplantier, J.F. Eggler, K.G.
Kraus, S.C. Marshall, A. Marfat, H. Masamune, J.T. Shirley,
J.E. Tickner, and J.P. Umland. Bioorg. Med. Chem. Lett. 5,
1969 (1995).
4. K. Kubo, Y. Inada, Y. Kohara, Y. Sugiura, M. Ojima, K. Itoh,
Y. Furukawa, K. Nishikawa, and T.J. Naka. J. Med. Chem. 36,
1772 (1993).
5. (a) M.J. Tebbe, W.A. Spitzer, F. Victor, S.C. Miller, C.C. Lee,
T.R. Sattelberg, E. McKinney, and J.C. Tang. J. Med. Chem.
40, 3937 (1997); (b) F. Victor, R. Loncharich, J. Tang, and
W.A. Spitzer. J. Med. Chem. 40, 3478 (1997); (c) F. Victor,
T.J. Brown, K. Campanale, B.A. Heinz, L.A. Shipley, K.S. Su,
J. Tang, L.M. Vance, and W.A. Spitzer. J. Med. Chem. 40,
1511 (1997).
6. (a) M.J. Plunkett and J.A. Ellman. J. Org. Chem. 62, 2885
(1997); (b) M.J. Plunkett and J.A. Ellman. J. Org. Chem. 60,
6006 (1995).
1h: Prepared from 2-butyraldehyde, 56%. HRMS calcd.
for C17H17N2O: 265.1335; found: 265.1343. 1H NMR
(CDCl3) d: 8.05 (s, 1H), 7.80 (m, 3H), 7.55 (m, 2H), 7.46 (t,
J = 7.9 Hz, 2H), 3.38 (quintet, J = 7.0 Hz, 1H), 1.47 (d, J =
6.8 Hz, 6H). 13C NMR (CDCl3) d: 197.1, 138.3, 132.0,
131.8, 130.0, 128.2, 124.9, 29.1, 21.3.
1i: Prepared from 1-hexanal, 68%. HRMS calcd. for
1
C19H21N2O: 293.1648; found: 293.1635. H NMR (CDCl3)
d: 8.25 (s, 1H), 7.85 (m, 2H), 7.77 (m, 2H), 7.51 (m, 4H),
3.36 (t, J = 7.6 Hz, 1H), 3.21 (m, 1H), 2.04 (m, 2H), 1.29
(m, 4H), 0.77 (t, J = 7.1 Hz, 3H). 13C NMR (CDCl3) d:
195.1, 156.3, 136.9, 135.5, 133.2, 132.9, 130.4, 129.9, 128.5,
127.7, 116.2, 113.9, 31.0, 27.3, 26.7, 22.0, 13.8.
7. T.L. Boehm, H.D.H. Showalter, M.J. Plunkett, and J.A.
Ellman. J. Org. Chem. 61, 6498 (1996).
8. F.X. Woolard, J. Paetsch, J.A. Ellman, and M.J. Plunkett. J.
Org. Chem. 62, 6102 (1997).
1j: Prepared from 3-phenylpropanal, 61%. HRMS calcd.
for C22H19N2O: 327.1492; found: 327.1495. 1H NMR (MeOH-
d4) d: 7.99 (s, 1H), 7.88 (m, 1H), 7.75 (m, 1H), 7.70 (m,
2H), 7.56 (m, 1H), 7.45 (m, 2H), 7.21 (m, 3H), 7.13 (m,
2H), 3.43 (t, J = 5.9 Hz, 2H), 3.17 (t, J = 6.0 Hz, 2H). 13C
NMR (MeOH-d4) d: 196.9, 157.6, 139.9, 138.6, 137.1,
135.1, 134.3, 132.3, 131.2, 130.1, 129.9, 129.4, 129.1, 128.4,
117.1, 114.9, 34.1, 30.2.
9. B. Chenera, J.A. Finkelstein, and D.F. Veber. J. Am. Chem.
Soc. 117, 11999 (1995).
10. (a) J.P. Kilburn, J. Lau, and R.C.F. Jones. Tetrahedron Lett. 41,
5419 (2000); (b) A. Mazurov. Bioorg. Med. Chem. Lett. 10, 67
(2000); (c) T.S. Yokum, J. Alsina, and G. Barany. J. Comb.
Chem. 2, 282 (2000); (d) D. Tumelty, M.K. Schwarz, K. Cao,
and M.C. Needles. Tetrahedron Lett. 40, 6185 (1999); (e) D.
Tumelty, M.K. Schwarz, K. Cao, and M.C. Needles. Tetrahe-
dron Lett. 39, 7467 (1998); (f) J.P. Mayer, G.S. Lewis, C.
McGee, and D. Bankaitis-Davis. Tetrahedron Lett. 39, 6655
(1998).
11. (a) Y.-C. Chi and C.-M. Sun. Synlett, 591 (2000); (b) C.-M.
Yeh, C.-L. Tung, and C.-M. Sun. J. Comb. Chem. 2, 341
(2000); (c) C.G. Blettner, W.A. Koenig, G. Ruehter, W.
Stenzel, and T. Schotten. Synlett, 307 (1999).
1k: Prepared from cyclohexylcarboxaldehyde, 66%. HRMS
calcd. for C20H21N2O: 305.1648; found: 305.1659. 1H NMR
(MeOH-d4) d: 7.85 (s, 1H), 7.66 (s, 1H), 7.64 (m, 1H), 7.61
(dd, J = 6.8, 1.2 Hz, 1H), 7.52 (m, 2H), 7.42 (m, 2H), 2.84
(m, 1H), 2.01 (d, J = 11.2 Hz, 2H), 1.80 (m, 2H), 1.70 (m,
1H), 1.56 (m, 2H), 1.39 (m, 2H), 1.27 (m, 1H). 13C NMR
(MeOH-d4) d: 197.8, 138.8, 132.3, 131.8, 129.9, 128.4,
124.7, 38.9, 31.7, 26.1, 25.9.
12. (a) S.S. Kulp and M.J. McGee. J. Org. Chem. 48, 4097 (1983);
(b) A. Donetti, O. Boniardi, and A. Ezhaya. Synthesis. 1009
(1980).
13. N. Miyarura and A. Suzuki. Chem. Rev. 95, 2457 (1995).
14. Y. Hu, J.A. Porco, Jr., J.W. Labadie, O.W. Gooding, and B.M.
Trost. J. Org. Chem. 63, 4518 (1998).
Acknowledgments
15. J.J.V. Eynde, F. Delfosse, and Y.V. Haverbeke. Tetrahedron,
51, 5813 (1995).
Funding for this project was provided to K.D.J. by The
Skaggs Institute for Chemical Biology, The Scripps Research
© 2001 NRC Canada