New octahydropyrido[3,4-b]acridine scaffolds for combinatorial chemistry

Article abstract of DOI:10.1055/s-2008-1067148

Friedlaender reaction of aminobromobenzaldehydes with an optically active decahydroisoquinolone building block gave new octahydropyrido[3,4-b] acridines with quantitative regioselectivity. The products define a platform for combinatorial chemistry. Bromine functions could be reacted further using Suzuki, Heck, Sonogashira, and Buchwald-Hartwig reactions as well as cyanations. The secondary amino function was deprotected and coupled with amino acids and benzoic acid derivatives. A small model library has been prepared. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067148

PAPER
2199
New Octahydropyrido[3,4-b]acridine Scaffolds for Combinatorial Chemistry
??? laas Lüder Diedrich, Detlev Haase, Jens Christoffers*
Institut für Reine und Angewandte Chemie, Universität Oldenburg, Carl-von-Ossietzky-Str. 9–11, 26111 Oldenburg, Germany
Fax +49(441)7983873; E-mail: jens.christoffers@uni-oldenburg.de
Received 15 April 2008
Dedicated to Professor R. W. Hoffmann on the occasion of his 75th birthday
Since quinoline derivatives are ubiquitous structural
Abstract: Friedländer reaction of aminobromobenzaldehydes with
motifs in medicinal chemistry,4 we were interested in
whether we could apply the heteroannulated bromoquino-
an optically active decahydroisoquinolone building block gave new
octahydropyrido[3,4-b]acridines with quantitative regioselectivity.
The products define a platform for combinatorial chemistry. Bro-
line 8 as a platform for the preparation of a model library
mine functions could be reacted further using Suzuki, Heck, Sono- of compounds 7 with two points of diversity R1 and R2
(Scheme 2). Substituents R1 would result from cross-cou-
gashira, and Buchwald–Hartwig reactions as well as cyanations.
pling reactions and substituents R2 from an amidation re-
The secondary amino function was deprotected and coupled with
amino acids and benzoic acid derivatives. A small model library has
action. Building block 9 has previously been prepared by
been prepared.
us on a multigram scale by an asymmetric Michael reac-
Key words: annulation, combinatorial chemistry, cross coupling,
piperidines, quinolines
tion, aldol condensation, and catalytic hydrogenation se-
quence, in analogy to the route from 1,5-diketones 1 to
bicyclic ketones 4.5
The asymmetric Michael reaction of cyclic b-oxo esters
with methyl vinyl ketone is a valuable tool for the large-
scale preparation of optically active compounds 1 con-
taining a quaternary stereocenter.1 These materials with a
five-, six-, or seven-membered ring are converted in two
steps (aldol condensation and catalytic hydrogenation)
into bicyclic ketones 4 with trans-annulated rings. We
have recently reported regioselective Friedländer quino-
line [with 2-aminobenzaldehyde (3a)] and Fischer indole
syntheses [with phenylhydrazine (5)] starting from these
cyclic ketones 4 (Scheme 1). Interestingly, the heteroan-
nulation yielded only linear products with quantitative re-
gioselectivity in the case of indoles 6 when starting with
trans-configurated bicycles 4.2 Synthesis of quinolines 2
proceeded with good to moderate regioselectivity.3
R1
Br
O
N
N
H
H
O
H
CO2Me
N
CO2Me
CO2Me
Br
CHO
NH2
Boc
N
N
7
8
9
Boc
R2
3b,c
Scheme 2 Proposal of octahydropyrido[3,4-b]acridine 8 as a plat-
form for a model library 7; compounds 8 are prepared by Friedländer
quinoline synthesis from building block 9 and aminobromoaldehydes
3b,c
O
O
Me
E
n
1
1. aldol reaction 2. hydrogenation
O
N
HN
H
H
H
E
E
E
CHO
NHNH2
n
n
n
2
4
6
NH2
5
3a
Scheme 1 Friedländer quinoline and Fischer indole syntheses from optically active bicyclic trans-ketones 4 (n = 0, 1, 2; E = CO2Et, CO2Me)
SYNTHESIS 2008, No. 14, pp 2199–2210
x
x.
x
x
.
2
0
0
8
Advanced online publication: 18.06.2008
DOI: 10.1055/s-2008-1067148; Art ID: C01508SS
© Georg Thieme Verlag Stuttgart · New York

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C. L. Diedrich et al.
PAPER
Nitration of 3-bromobenzaldehyde (10) proceeded very
conveniently when potassium nitrate/sulfuric acid was
used (Scheme 3).6 As also reported by others,7 compound
11a was obtained as the major product. After chromato-
graphic separation, regioisomer 11b was isolated as a
byproduct. This compound has been prepared before by
oxidation of the respective bromonitrotoluene,8 but it has
never been reported to be a product of the nitration of 10.
We did not detect other regioisomers of products 11a and
11b. For the reduction of the nitro group we adopted the
protocol used for the preparation of 2-aminobenzaldehyde
(3a).3,9 Compound 3b has been previously reported and
used for the Friedländer quinoline synthesis.7 Isomer 3c
was reported once previously and in that case it was pre-
pared by reduction of the corresponding benzonitrile de-
rivative.10 Before reacting aldehydes 3b and 3c with
carbamate-protected oxo ester 9, the reaction conditions
and regioselectivity were investigated with compound 3a,
which was always freshly prepared from nitrobenzalde-
hyde prior to use. When applying standard conditions3,9
tetracyclic product 8a was obtained in acceptable yield
and, more importantly, as a single regioisomer. No angu-
lar annulation product was detectable, as observed by us
in cases of oxo esters 4 earlier.3 The structure was proved
by single crystal X-ray structure analysis; an ORTEP plot
of the molecular structure is depicted in Figure 1.11 Sub-
sequently, bromoaldehydes 3b and 3c were reacted under
the same conditions with bicyclic ketone 9. Both bromo-
substituted octahydropyrido[3,4-b]acridines 8b and 8c
were obtained in even better yields. Since starting materi-
al 9 was used in enantiopure form, compounds 8a, 8b, and
8c and all subsequent products are optically active. Due to
E/Z isomerism of the carbamate N–C bond, a partly dou-
bled signal set was observed in the NMR spectra of all N-
tert-butoxycarbonyl-protected compounds.
CHO
Br
CHO
Br
CHO
NO2
a)
+
NO2
Br
11b (14%)
10
11a (68%)
b)
b)
CHO
NH2
CHO
Br
CHO
NH2
NH2
Br
3c (97%)
3b (98%)
3a
c)
c)
c)
Br
Br
N
N
N
H
H
H
CO2Me
CO2Me
CO2Me
N
N
N
Boc
8a (74%)
Boc
8b (83%)
Boc
8c (85%)
Scheme
3
Synthesis of octahydropyrido[3,4-b]acridines 8.
Reagents and conditions: (a) KNO3 (3 equiv), H2SO4 (20 equiv), 23
°C, 16 h; (b) Fe powder (10 equiv), H2O–EtOH, 100 °C, 1.5 h. (c) oxo
ester 9 (1 equiv), NaOH (0.5 equiv), MeOH, 110 °C (tightly closed
reaction vial), 1.5 h.
was introduced as a highly active, water-soluble catalyst
for Suzuki couplings.14 Indeed, only 1.3 mol% sodium tet-
rachloropalladate(II) and 1.5 mol% cataCXium FSulf
were required to achieve the same yields of products 13a
(entry 2) and 13f (entry 10).
The Heck reaction was performed with 8b and styrene to
give product 13c as single stereoisomer (single signal set
in NMR, we presume E configuration of the olefinic dou-
ble bond). With standard catalyst [10 mol% Pd(OAc)2, 24
mol% PPh3]15 the yield was 67% (entry 4), however, using
1 mol% cataCXium C16 gave an increased yield of 13c of
80% (entry 5).
Figure 1 ORTEP representation of the molecular structure of octa-
hydropyrido[3,4-b]acridine derivative 8a in the solid state
The first cross-coupling reaction investigated was the
Suzuki coupling of 8b and 8c catalyzed by palladium on
charcoal (2–4 mol% with respect to starting materials)
with phenylboronic acid and its derivatives (Scheme 4).12
Phenylboronic acid gave good yields (87% and 71% for
13a and 13f, respectively, Table 1, entries 1 and 9) in both
cases. Using 4-methoxyphenylboronic acid gives about
the same yield (86% for 13b, entry 3), with 4-(trifluoro-
methyl)phenylboronic acid the result was significantly
improved (93% for 13g, entry 11). Very recently, sodium
tetrachloropalladate(II) with ligand cataCXium FSulf13
Buchwald–Hartwig amination of 8b with cyclohexyl-
amine under standard conditions17 [5 mol% Pd(OAc)2, 7.5
mol% BINAP] gave product 13d in 57% yield (entry 6),
but the use of 4 mol% Pd(OAc)2 and 7 mol% cataCXium
PintB18 increased the yield of 13d to 70% (entry 7).
Aniline was coupled with heterocycle 8c. In this case the
BINAP ligand gave better results (55% of 13i, entry 14)
than cataCXium PintB (16%, entry 15).
Sonogashira coupling of compound 8c with phenylacety-
lene gave 13h in 38% yield (entry 12) (4 mol%
PdCl2(PPh3)2, 4 mol% CuI, and 4.5 mol% PPh3).19 Using
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New Octahydropyrido[3,4-b]acridine Scaffolds for Combinatorial Chemistry
2201
R1
1.6 mol% Na2PdCl4, 2.5 mol% CuI, and 2.3 mol%
cataCXium FBu gave an increased yield of 13h of 51%
(entry 13).20
Finally, a new method21 for copper-catalyzed cyanation of
heteroaryl bromides was tried with both, compounds 8b
and 8c. Unfortunately, the results were disappointing
(22% yield of 13e, entry 8, and 31% yield of 13j, entry
16).21
R1
Br
a)
N
N
N
c)
H
O
H
H
CO2Me
CO2Me
CO2Me
N
N
N
X
Boc
8b
R2
For six compounds 13a–d, 13g, and 13h, N-deprotection
and amidation was investigated. Cleavage of the Boc
group was achieved with neat trifluoroacetic acid at 23 °C
within one hour. Compounds 14a–f (see Table 2) were
13a–e (X = Boc)
14a–d (X = H)
b)
7a–d
R1
N
1
Br
R1
isolated by extraction and their purity (by H NMR) ex-
ceeds 95%. Yields are generally quantitative (88–99%),
except for compound 14e (73%, entry 5). Coupling reac-
tions of compounds 14a–e were performed with N,N¢-di-
cyclohexylcarbodiimide and 1-hydroxy-1H-benzotriazole
(HOBt) in dichloromethane at 23 °C. After stirring over-
night, yields were generally quantitative (95–97%), ex-
cept for compound 14e, which required three days to give
a 60% yield of the isolated product 7e (entry 5). Three
amino acid derivatives were used as carboxylic acids: N-
[(9H-fluoren-9-ylmethoxy)carbonyl]-b-alanine (Fmoc-b-
Ala, entry 1), 2-[(tert-butoxycarbonyl)amino]isobutyric
acid (Boc-Aib, entry 2),22 and N-[(9H-fluoren-9-yl-
N
N
a)
c)
H
O
H
H
CO2Me
CO2Me
CO2Me
N
N
X
N
Boc
8c
R2
7e,f
13f–j (X = Boc)
14e,f (X = H)
b)
Scheme 4 Cross coupling reactions, deprotection and amidation,
for yields see Tables 1 and 2. Reagents and conditions: (a) see Table
methoxy)carbonyl]-L-neopentylglycine23 (Fmoc-Npg, en- 1; (b) TFA (70–100 equiv, as solvent), 23 °C, 1 h; (c) DCC (1.1
try 5). Reactions with benzoic acid (entry 3) and its
electron-rich derivative (entry 4) proceeded without any
problems. Interestingly, the amidation of 14d took place
equiv), HOBt (1.1 equiv), CH2Cl2, 23 °C, 16 h (for 14a–d), 3 d (for
14e), compound 14f was reacted with an acid chloride: Et3N (2.2
equiv), CH2Cl2, r.t., 16 h.
regioselectively at N2 (entry 4), as is evidenced by com-
paring the 1H and 13C chemical shifts of the quinoline part
equal. Amidation of the exocyclic arylamine function
of starting material 14d and product 7d, which are about would have resulted in an electronic influence on the
Table 1 Cross-Coupling Reactions
Entry Substrate Nucleophile R1Y
Conditions (equiv)
Product Yield (%)
1
2
8b
PhB(OH)2
Pd-C (0.024), K2CO3, H2O–i-PrOH, 85 °C, 16 h
Na2PdCl4 (0.013), cataCXium FSulf (0.015), K2CO3, H2O–BuOH, 100 °C, 20 h
13a
87
89
3
8b
8b
4-MeOC6H4B(OH)2
PhCH=CHH
Pd-C (0.031), K2CO3, H2O–i-PrOH, 85 °C, 16 h
13b
13c
86
4
5
Pd(OAc)2 (0.1), PPh3 (0.24), Et3N, DMF, 100 °C, 18 h
cataCXium C (0.01), Et3N, DMF, 100 °C, 18 h
67
80
6
7
8b
CyNH2
Pd(OAc)2 (0.05), BINAP (0.075), NaOt-Bu, toluene, 85 °C, 16 h
Pd(OAc)2 (0.04), cataCXium PIntB (0.07), NaOt-Bu, toluene, 120 °C, 20 h
13d
57
70
8
8b
8c
K4[Fe(CN)6] (R1 = CN) CuI (0.1), Buim (2),a toluene, 160 °C,b 16 h
13e
13f
22
9
10
PhB(OH)2
Pd-C (0.022), K2CO3, H2O–i-PrOH, 85 °C, 16 h
71
71
Na2PdCl4 (0.013), cataCXium FSulf (0.015), K2CO3, H2O–BuOH, 100 °C, 20 h
11 8c
4-F3CC6H4B(OH)2
Pd-C (0.027), K2CO3, H2O–i-PrOH, 85 °C, 16 h
13g
13h
93
12 8c
13
PhC≡CH
PdCl2(PPh3)2 (0.04), CuI (0.04), PPh3 (0.045), i-Pr2NEt, 100 °C, 16 h
Na2PdCl4 (0.016), cataCXium FBu (0.023), CuI (0.025), i-Pr2NH, 80 °C, 20 h
38
51
14 8c
15
PhNH2
Pd(OAc)2 (0.05), BINAP (0.07), NaOt-Bu, toluene, 85 °C, 16 h
Pd(OAc)2 (0.04), cataCXium PIntB (0.07), NaOt-Bu, toluene, 110 °C, 20 h
13i
13j
55
16
16 8c
K4[Fe(CN)6] (R1 = CN) CuI (0.1), Buim (2),a toluene, 160 °C,b 16 h
31
a Buim = 1-butyl-1H-imidazole.
b Tightly closed reaction vial.
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C. L. Diedrich et al.
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Table 2 Deprotection and Amidation
Entry
Starting
material
R1
Deprotection
Product
R2COOH
Amide
Yield (%)
Product
Yield (%)
1
2
3
4
5
6
13a
13b
13c
13d
13g
13h
Ph
14a
14b
14c
14d
14e
14f
95
93
97
99
73
88
Fmoc-b-Ala
Boc-Aib
7a
7b
7c
7d
7e
7f
95
98
97
97
60
59
4-MeOC6H4
CH=CHPh
NHCy
PhCO2H
4-MeOC6H4CO2H
Fmoc-L-Npg
3-O2NC6H4COCla
4-F3CC6H4
C≡CPh
a Amidation with Et3N as a base.
(silica gel, PE–EtOAc, 3:1). 5-Bromo isomer 11a (4.24 g, 68%,
Rf = 0.72) was obtained in the first fraction (mp 66 °C). Secondly,
3-bromo isomer 11b (0.82 g, 14%, Rf = 0.38) was eluted (mp 76 °C)
both as pale yellow crystals. Spectroscopic data of 5-bromo-2-ni-
trobenzaldehyde (11a)24 and 3-bromo-2-nitrobenzaldehyde (11b)8
are in accordance with the literature.
quinoline moiety. For the preparation of amide 7f (entry
6) we used the electron-poor acid chloride, but the yield
was not fully satisfactory (59%).
Octahydropyrido[3,4-b]acridines 8 have been prepared by
Friedländer reaction of aminobenzaldehydes 3 with opti-
cally active building block 9. Regioisomeric compounds
8b and 8c with an sp2-bromine are attractive platforms for
combinatorial chemistry. The first step of further func-
tionalization was a cross-coupling reaction. In particular,
palladium-catalyzed Suzuki couplings, Buchwald–
Hartwig aminations, the Heck reaction, the Sonogashira
coupling, and copper-catalyzed cyanations were per-
formed. The second step was, after cleavage of the tert-
butoxycarbonyl protective group, amination with differ-
ent amino acid and benzoic acid derivatives. A number of
examples of a model library was prepared.
2-Amino-5-bromobenzaldehyde (3b); Typical Procedure
Fe powder (838 mg, 15.0 mmol, 10 equiv), H2O (1.5 mL), and
concd HCl (25 mg) were added to a soln of aldehyde 11a (345 mg,
1.50 mmol) in EtOH (10 mL). The mixture was heated to reflux and
stirred vigorously for 90 min. The mixture was cooled to r.t., EtOAc
(50 mL) was added, the resulting mixture was dried (MgSO4) and
filtered, and the solvent was evaporated to give 3b (295 mg, 98%)
as a yellow solid, mp 64 °C. According to 1H NMR the purity was
>95%. The material was used without further purification. It shows
no long-term stability at ambient conditions.
IR (ATR): 3431 (s), 3329 (s), 1667 (vs), 1547 (s), 1469 (s), 1390
(m), 1287 (s), 1159 (m), 887 (w), 822 (m), 711 (m) cm–1.
1H NMR (500 MHz, CDCl3): d = 6.13 (br s, 2 H), 6.56 (d, J = 8.8
Hz, 1 H), 7.36 (dd, J = 2.4 Hz, J = 8.8 Hz, 1 H), 7.57 (d, J = 2.4 Hz,
1 H), 9.79 (s, 1 H).
13C{1H} NMR (125 MHz, CDCl3): d = 107.23 (C), 117.98 (CH),
119.95 (C), 137.41 (CH), 137.87 (CH), 148.68 (C), 192.75 (CH).
HRMS (EI): m/z [M]+ calcd for C7H6BrNO: 198.9633; found:
198.9633.
Preparative column chromatography was carried out using Merck
silica gel (0.035–0.070 mm, type 60 A) with petroleum ether (PE,
bp 40–60 °C) and EtOAc as eluents. TLC was performed on Merck
silica gel F254 plates on aluminum sheets. 1H and 13C NMR spectra
were recorded on a Bruker Avance DRX 500 and Avance DPX 300.
Multiplicities of carbon signals were determined with DEPT exper-
iments. MS and HRMS spectra were obtained with a Finnigan MAT
95 (EI and CI) and Waters Q-TOF Premier (ESI) spectrometer. IR
spectra were recorded on a Bruker Tensor 27 spectrophotometer
equipped with a GoldenGate diamond-ATR unit. Elemental analy-
ses were measured with a Euro EA-CHNS from HEKAtech and op-
tical rotations with a Perkin Elmer polarimeter 343. All starting
materials were commercially available, except Boc-Aib22 and
Fmoc-Npg,23 which were prepared according to literature proce-
dures. Compounds 3b7 and 3c10 were previously reported without
spectroscopic data. The preparation and data of compound 9 was
previously reported by us.5
Anal. Calcd for C7H6BrNO (200.03): C, 42.03; H, 3.02; N, 7.00.
Found: C, 41.44; H, 2.95; N, 6.79.
2-Amino-3-bromobenzaldehyde (3c)
Following the typical procedure for 3b using aldehyde 11b (720
mg, 3.13 mmol), Fe powder (1.75 g, 31.3 mmol, 10 equiv), and
concd HCl (59 mg) in EtOH (30 mL) and H2O (3 mL) gave alde-
hyde 3c (610 mg, 97%) as a yellow solid; mp 40 °C. According to
1H NMR the purity was >95%. The material was used without fur-
ther purification. It shows no long term stability at ambient condi-
tions.
5-Bromo-2-nitrobenzaldehyde (11a) and 3-Bromo-2-nitro-
benzaldehyde (11b)
IR (ATR): 3471 (m), 3339 (m), 1663 (vs), 1607 (vs), 1578 (s), 1538
(s), 1445 (m), 1199 (s), 1144 (m), 1063 (m), 885 (m), 769 (m), 728
(m), 669 (s) cm–1.
1H NMR (500 MHz, CDCl3): d = 6.65 (br s, 2 H), 6.66 (t, J = 7.7
Hz, 1 H), 7.47 (dd, J = 1.4 Hz, J = 7.7 Hz, 1 H), 7.61 (dd, J = 1.4
Hz, J = 7.7 Hz, 1 H), 9.92 (s, 1 H).
KNO3 (7.80 g, 77.3 mmol) was dissolved in cooled (ice H2O bath)
H2SO4 (60.0 g, 612 mmol), while keeping the temperature of the
mixture below 30 °C. 3-Bromobenzaldehyde (10, 5.00 g, 27.0
mmol) was then slowly added, while the temperature was kept be-
low 30 °C. The mixture was further stirred at 23 °C for 16 h, then
H2O (100 mL) was carefully added and the resulting mixture ex-
tracted with CH2Cl2 (3 × 80 mL). The combined organic layers
were washed with sat. aq NaHCO3 (50 mL), dried (MgSO4), and fil-
tered. The solvent was evaporated and the residue chromatographed
13C{1H} NMR (125 MHz, CDCl3): d = 110.08 (C), 116.80 (CH),
119.56 (C), 135.27 (CH), 137.93 (CH), 146.89 (C), 193.18 (CH).
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New Octahydropyrido[3,4-b]acridine Scaffolds for Combinatorial Chemistry
2203
HRMS (EI): m/z [M]+ calcd for C7H6BrNO: 198.9633; found:
Anal. Calcd for C23H27BrN2O4 (475.38): C, 58.11; H, 5.72; N, 5.89.
198.9632.
Found: C, 57.30; H, 5.78; N, 5.74.
Anal. Calcd for C7H6BrNO (200.03): C, 42.03; H, 3.02; N, 7.00.
Found: C, 41.81; H, 3.03; N, 6.86.
2-tert-Butyl 12a-Methyl (4aS,12aR)-7-Bromo-
1,2,3,4,4a,5,12,12a-octahydropyrido[3,4-b]acridine-2,12a-di-
carboxylate (8c)
Following the typical procedure for 8a using freshly prepared alde-
hyde 3c (610 mg, 3.05 mmol, 1.05 equiv), NaOH (67 mg, 1.68
mmol, 0.5 equiv), oxo ester 9 (900 mg, 2.89 mmol), and MeOH (7
mL). Chromatography (silica gel, PE–EtOAc, 1:1, Rf = 0.44) gave
8c (1.17 g, 85%) as a colorless solid; mp 94 °C.
2-tert-Butyl 12a-Methyl (4aS,12aR)-1,2,3,4,4a,5,12,12a-Octahy-
dropyrido[3,4-b]acridine-2,12a-dicarboxylate (8a); Typical
Procedure
A soln of freshly prepared aldehyde 3a (170 mg, 1.41 mmol, 1.3
equiv), NaOH (22 mg, 0.55 mmol, 0.5 equiv), and oxo ester 9 (340
mg, 1.10 mmol) in MeOH (6 mL) was stirred at 110 °C for 90 min
in a tightly closed reaction vial. The mixture was cooled to r.t.,
CH2Cl2 (20 mL) was added, and the soln was washed with H2O (10
mL). The soln was dried (MgSO4) and filtered and the solvent was
evaporated to give a residue that was chromatographed (silica gel,
PE–EtOAc, 1:1, Rf = 0.32) to give 8a (320 mg, 74%) as a colorless
solid; mp 213–214 °C; single crystals were grown from hexane–
EtOAc.
[a]D20 +23.5 (c 2.5, CH2Cl2).
IR (ATR): 2977 (w), 2948 (w), 2858 (w), 1730 (m), 1688 (vs), 1426
(s), 1365 (m), 1239 (m), 1162 (vs), 1127 (vs), 1025 (m), 761 (m)
cm–1.
1H NMR (500 MHz, CDCl3): d = 1.45 (s, 9 H), 1.60–1.76 (m, 1 H),
2.04–2.12 (m, 1 H), 2.15–2.28 (m, 1 H), 2.58–3.00 (m, 2 H), 2.74
(d, J = 16.1 Hz, 1 H), 3.31 (d, J = 9.1 Hz, 2 H), 3.36–3.48 (m, 1 H),
3.53 (s, 3 H), 4.20–4.42 (m, 1 H), 4.56–4.76 (m, 1 H), 7.28 (t,
J = 7.8 Hz, 1 H), 7.66 (d, J = 8.1 Hz, 1 H), 7.82 (s, 1 H), 7.94 (d,
J = 7.4 Hz, 1 H).
[a]D20 +72 (c 5.5, CH2Cl2).
IR (ATR): 2976 (w), 2924 (w), 2856 (w), 1730 (m), 1693 (vs), 1427
(s), 1278 (m), 1241 (m), 1166 (s), 754 (w) cm–1.
1H NMR (500 MHz, CDCl3): d = 1.46 (s, 9 H), 1.67–1.74 (m, 1 H),
2.02–2.12 (m, 1 H), 2.12–2.32 (m, 1 H), 2.60–2.92 (m, 2 H), 2.75
(d, J = 16.0 Hz, 1 H), 3.18–3.32 (m, 2 H), 3.36–3.50 (m, 1 H), 3.53
(s, 3 H), 4.20–4.48 (m, 1 H), 4.60–4.76 (m, 1 H), 7.44 (t, J = 7.4 Hz,
1 H), 7.62 (t, J = 7.2 Hz, 1 H), 7.70 (d, J = 8.1 Hz, 1 H), 7.83 (s, 1
H), 7.96 (d, J = 8.5 Hz, 1 H).
13C{1H} NMR (125 MHz, CDCl3): d = 27.89 (CH2), 28.27 (3 CH3),
37.06 (CH2), 37.56 (CH2), 39.90 (CH), 43.70 (0.5 CH2), 44.83 (0.5
CH2), 45.43 (C), 51.72 (CH3), 52.27 (0.5 CH2), 53.19 (0.5 CH2),
79.51 (C), 123.84 (C), 126.00 (CH), 126.89 (CH), 128.06 (C),
128.73 (C), 132.31 (CH), 135.47 (CH), 143.78 (C), 153.86 (C),
158.76 (C), 172.76 (C).
13C{1H} NMR (125 MHz, CDCl3): d = 28.01 (CH2), 28.26 (3 CH3),
36.88 (CH2), 37.81 (CH2), 39.97 (CH), 43.60 (0.5 CH2), 44.91 (0.5
CH2), 45.50 (C), 51.65 (CH3), 52.53 (0.5 CH2), 53.30 (0.5 CH2),
79.48 (C), 125.68 (CH), 126.87 (CH), 126.88 (C), 127.65 (C),
128.26 (CH), 128.79 (CH), 135.11 (CH), 146.86 (C), 154.26 (C),
157.34 (C), 172.81 (C).
HRMS (CI, isobutane): m/z [M + H]+ calcd for C23H28BrN2O4:
475.1232; found: 475.1233.
Anal. Calcd for C23H27BrN2O4 (475.38): C, 58.11; H, 5.72; N, 5.89.
Found: C, 57.72; H, 5.73; N, 5.86.
Suzuki Coupling; General Procedure A
HRMS (CI, isobutane): m/z [M + H]+ calcd for C23H29N2O4:
397.2127; found: 397.2127.
A suspension of aryl bromide 8 (230 mmol), boronic acid (300 mmol,
1.3 equiv), 10% Pd-C (ca. 6 mg, 5.6 mmol, 2.4 mol%), and K2CO3
(3 equiv) in i-PrOH (1.5 mL) and H2O (1 mL) was degassed and
flushed with N2. The mixture was then heated to 85 °C for 16 h. The
mixture was filtered, H2O (10 mL) was added, and the mixture was
extracted with CH2Cl2 (3 × 15 mL). The organic phase was dried
(MgSO4) and filtered and the solvent was evaporated. The crude
product was purified by chromatography (silica gel).
2-tert-Butyl 12a-Methyl (4aS,12aR)-9-Bromo-
1,2,3,4,4a,5,12,12a-octahydropyrido[3,4-b]acridine-2,12a-di-
carboxylate (8b)
Following the typical procedure for 8a using freshly prepared alde-
hyde 3b (610 mg, 3.05 mmol, 1.05 equiv), NaOH (67 mg, 1.68
mmol, 0.5 equiv), oxo ester 9 (900 mg, 2.89 mmol), and MeOH (7
mL). Chromatography (silica gel, PE–EtOAc, 1:1, Rf = 0.36) gave
8b (1.15 g, 83%) as a colorless solid; mp 207 °C.
2-tert-Butyl 12a-Methyl (4aS,12aR)-1,2,3,4,4a,5,12,12a-Octahy-
dro-9-phenylpyrido[3,4-b]acridine-2,12a-dicarboxylate (13a)
A mixture of 8b (50 mg, 105 mmol), PhB(OH)2 (14 mg, 115 mmol,
1.1 equiv), Na2PdCl4 (0.4 mg, 1.4 mmol, 1.3 mol%), cataCXium
FSulf (1.1 mg, 1.5 mmol, 1.5 mol%), and K2CO3 (44 mg, 315 mmol,
3 equiv) was placed in a Schlenk tube, evacuated and flushed with
N2 (2 ×). Degassed H2O (0.5 mL) and BuOH (0.5 mL) were added
and the resulting soln stirred at 100 °C for 16 h. The mixture was
cooled to r.t., the organic phase was separated, and the aqueous
phase was extracted with CH2Cl2 (1 × 5 mL). The combined organic
phases were dried (MgSO4) and filtered and the solvents were evap-
orated to give a residue that was purified by chromatography (silica
gel, PE–EtOAc, 1:1, Rf = 0.22) to give 13a (44 mg, 89%) as a col-
orless solid (mp 216 °C).
[a]D20 +117 (c 5.4, CH2Cl2).
IR (ATR): 2978 (w), 2946 (w), 2857 (w), 1730 (m), 1689 (vs), 1428
(s), 1401 (m), 1275 (m), 1238 (m), 1195 (s), 1160 (s), 1127 (s), 982
(m), 825 (s), 764 (m) cm–1.
1H NMR (500 MHz, CDCl3): d = 1.46 (s, 9 H), 1.59–1.74 (m, 1 H),
2.03–2.13 (m, 1 H), 2.14–2.31 (m, 1 H), 2.57–2.94 (m, 2 H), 2.75
(d, J = 16.1 Hz, 1 H), 3.13–3.29 (m, 2 H), 3.35–3.47 (m, 1 H), 3.54
(s, 3 H), 4.20–4.48 (m, 1 H), 4.68–4.79 (m, 1 H), 7.68 (dd, J = 2.0
Hz, J = 9.0 Hz, 1 H), 7.74 (s, 1 H), 7.82 (d, J = 9.0 Hz, 1 H), 7.86
(d, J = 2.0 Hz, 1 H).
13C{1H} NMR (125 MHz, CDCl3): d = 27.98 (CH2), 28.25 (3 CH3),
36.83 (CH2), 37.79 (CH2), 39.90 (CH), 43.56 (0.5 CH2), 44.87 (0.5
CH2), 45.39 (C), 51.70 (CH3), 52.36 (0.5 CH2), 53.22 (0.5 CH2),
79.52 (C), 119.35 (C), 127.93 (C), 128.81 (C), 128.82 (CH), 130.03
(CH), 132.15 (CH), 134.00 (CH), 145.34 (C), 154.15 (C), 157.92
(C), 172.70 (C).
Alternative procedure: Following general procedure A, 8b (110
mg, 230 mmol), PhB(OH)2 (36 mg, 300 mmol, 1.3 equiv), 10% Pd-
C (6 mg, 5.6 mmol, 2.4 mol%), and K2CO3 (87 mg, 630 mmol, 3
equiv) were reacted to give 13a (96 mg, 87%).
[a]D20 +152 (c 7.7, CH2Cl2).
HRMS (CI, isobutane): m/z [M + H]+ calcd for C23H28BrN2O4:
475.1232; found: 475.1233.
IR (ATR): 2976 (w), 2951 (w), 2859 (w), 1729 (s), 1687 (vs), 1426
(s), 1240 (m), 1165 (vs), 1127 (m), 731 (m) cm–1.
Synthesis 2008, No. 14, 2199–2210 © Thieme Stuttgart · New York

2204
C. L. Diedrich et al.
PAPER
1H NMR (500 MHz, CDCl3): d = 1.46 (s, 9 H), 1.60–1.74 (m, 1 H),
2.04–2.14 (m, 1 H), 2.16–2.32 (m, 1 H), 2.60–2.96 (m, 2 H), 2.77
(d, J = 16.0 Hz, 1 H), 3.18–3.34 (m, 2 H), 3.36–3.49 (m, 1 H), 3.54
(s, 3 H), 4.20–4.50 (m, 1 H), 4.56–4.80 (m, 1 H), 7.34 (t, J = 7.4 Hz,
1 H), 7.48 (t, J = 7.6 Hz, 2 H), 7.68 (d, J = 7.2 Hz, 2 H), 7.87–7.93
(m, 3 H), 8.05 (d, J = 7.9 Hz, 1 H).
13C{1H} NMR (125 MHz, CDCl3): d = 28.04 (CH2), 28.28 (3 CH3),
36.87 (CH2), 37.86 (CH2), 39.99 (CH), 43.63 (0.5 CH2), 44.90 (0.5
CH2), 45.51 (C), 51.69 (CH3), 52.44 (0.5 CH2), 53.30 (0.5 CH2),
79.51 (C), 124.54 (CH), 126.88 (C), 127.03 (C), 127.18 (2 CH),
127.46 (CH), 128.10 (C, br.), 128.57 (CH), 128.67 (CH), 128.80 (2
CH), 135.35 (CH), 138.39 (C), 140.30 (C), 146.21 (C), 157.37 (C),
172.82 (C).
(d, J = 16.1 Hz, 1 H), 3.20–3.32 (m, 2 H), 3.34–3.46 (m, 1 H), 3.54
(s, 3 H), 4.19–4.46 (m, 1 H), 4.58–4.77 (m, 1 H), 7.23 (s, 2 H), 7.28
(t, J = 7.4 Hz, 1 H), 7.38 (t, J = 7.5 Hz, 2 H), 7.55 (d, J = 8.0 Hz, 2
H), 7.71 (s, 1 H), 7.83 (br s, 1 H), 7.88–7.92 (m, 1 H), 7.94–8.02 (m,
1 H).
13C{1H} NMR (125 MHz, CDCl3): d = 28.13 (CH2), 28.36 (3 CH3),
36.93 (CH2), 37.93 (CH2), 40.12 (CH), 43.67 (0.5 CH2), 45.02 (0.5
CH2), 45.62 (C), 51.79 (CH2), 52.62 (0.5 CH2), 53.45 (0.5 CH2),
79.63 (C), 125.26 (CH), 126.56 (2 CH), 126.72 (CH), 127.22 (C),
127.85 (CH), 128.01 (CH), 128.67 (CH), 128.73 (2 CH), 129.61
(CH), 134.83 (C), 135.18 (CH), 137.09 (C), 146.72 (C), 154.36 (C),
157.22 (C), 172.92 (C).
HRMS (CI, isobutane): m/z [M + H]+ calcd for C31H35N2O4:
499.2597; found: 499.2597.
HRMS (CI, isobutane): m/z [M + H]+ calcd for C29H33N2O4:
473.2440; found: 473.2440.
2-tert-Butyl 12a-Methyl (4aS,12aR)-9-(Cyclohexylamino)-
1,2,3,4,4a,5,12,12a-octahydropyrido[3,4-b]acridine-2,12a-di-
carboxylate (13d)
2-tert-Butyl 12a-Methyl (4aS,12aR)-1,2,3,4,4a,5,12,12a-Octahy-
dro-9-(4-methoxyphenyl)pyrido[3,4-b]acridine-2,12a-dicar-
boxylate (13b)
Following general procedure A using 8b (100 mg, 210 mmol), 4-
MeOC6H4B(OH)2 (45 mg, 300 mmol, 1.4 equiv), 10% Pd-C (7 mg,
6.6 mmol, 3.1 mol%), and K2CO3 (89 mg, 640 mmol, 3 equiv). Chro-
matography (silica gel, PE–EtOAc, 1:3, Rf = 0.42) gave 13b (90
mg, 86%) as a colorless solid; mp 189 °C.
A suspension of Pd(OAc)2 (1 mg, 4.5 mmol, 4 mol%) and
cataCXium PIntB (2.5 mg, 7.4 mmol, 7 mol%) in abs toluene (0.5
mL) was stirred for 5 min under an inert atmosphere. Compound 8b
(50 mg, 105 mmol), CyNH2 (13 mg, 131 mmol, 1.3 equiv), and
NaOt-Bu (17 mg, 177 mmol, 1.7 equiv) were added and the resulting
mixture was stirred at 120 °C for 20 h. The mixture was cooled to
r.t., CH2Cl2 (5 mL) was added, and the soln washed with sat. aq
NaHCO3 (5 mL). The organic phase was dried (MgSO4) and fil-
tered, all volatile materials were removed in vacuo, and the residue
was chromatographed (silica gel, EtOAc, Rf = 0.40) to give 13d (36
mg, 70%) as a yellow solid; mp 104 °C.
[a]D20 +150 (c 8.5, CH2Cl2).
IR (ATR): 2957 (w), 2930 (w), 2860 (w), 1730 (m), 1690 (s), 1608
(m), 1424 (m), 1242 (m), 1164 (vs), 1127 (m), 1022 (m), 825 (s),
729 (m) cm–1.
1H NMR (500 MHz, CDCl3): d = 1.45 (s, 9 H), 1.60–1.74 (m, 1 H),
2.02–2.12 (m, 1 H), 2.14–2.32 (m, 1 H), 2.56–2.96 (m, 2 H), 2.75
(d, J = 16.0 Hz, 1 H), 3.34–3.38 (m, 2 H), 3.38–3.48 (m, 1 H), 3.53
(s, 3 H), 3.86 (s, 3 H), 4.20–4.46 (m, 1 H), 4.56–4.78 (m, 1 H), 6.99–
7.03 (m, 2 H), 7.60–7.64 (m, 2 H), 7.83 (s, 1 H), 7.82–7.90 (m, 2 H),
7.99–8.02 (m, 1 H).
13C{1H} NMR (125 MHz, CDCl3): d = 28.09 (CH2), 28.31 (3 CH3),
36.85 (CH2), 37.90 (CH2), 40.06 (CH), 43.62 (0.5 CH2), 44.97 (0.5
CH2), 45.55 (C), 51.72 (CH3), 52.55 (0.5 CH2), 53.35 (0.5 CH2),
55.30 (CH3), 79.56 (C), 114.31 (2 CH), 123.74 (CH), 127.16 (C),
128.25 (C), 128.26 (2 CH), 128.50 (CH), 128.55 (CH), 132.81 (C),
135.31 (CH), 138.08 (C), 145.93 (C), 154.02 (C), 157.03 (C),
159.34 (C), 172.87 (C).
20
[a]D +114 (c 1.0, CH2Cl2).
IR (ATR): 3370 (w), 2929 (m), 2854 (w), 1727 (m), 1686 (s), 1624
(s), 1425 (s), 1383 (m), 1365 (m), 1234 (s), 1162 (vs), 1126 (vs),
821 (m), 729 (s) cm–1.
1H NMR (500 MHz, CDCl3): d = 1.12–1.30 (m, 3 H), 1.35–1.43 (m,
2 H), 1.44 (s, 9 H), 1.55–1.70 (m, 2 H), 1.74–1.81 (m, 2 H), 1.95–
2.05 (m, 1 H), 2.05–2.14 (m, 2 H), 2.15–2.30 (m, 1 H), 2.53–2.91
(m, 2 H), 2.65 (d, J = 15.9 Hz, 1 H), 3.06 (dd, J = 5.9 Hz, J = 17.8
Hz, 1 H), 3.17 (dd, J = 12.5 Hz, J = 17.8 Hz, 1 H), 3.25–3.38 (m, 2
H), 3.51 (s, 3 H), 3.60–4.04 (m, 1 H), 4.15–4.43 (m, 1 H), 4.53–4.73
(m, 1 H), 6.57 (d, J = 2.3 Hz, 1 H), 6.95 (dd, J = 2.5 Hz, J = 9.0 Hz,
1 H), 7.56 (s, 1 H), 7.70 (d, J = 9.0 Hz, 1 H).
13C{1H} NMR (125 MHz, CDCl3): d = 24.90 (2 CH2), 25.80 (CH2),
28.07 (CH2), 28.27 (3 CH3), 32.99 (CH2), 33.09 (CH2), 36.37 (CH2),
37.98 (CH2), 40.09 (CH), 43.74 (0.5 CH2), 44.97 (0.5 CH2), 45.56
(C), 51.57 (CH), 51.66 (CH3), 52.57 (0.5 CH2), 53.40 (0.5 CH2),
79.41 (C), 102.41 (CH), 121.23 (CH), 127.54 (C), 128.69 (C),
129.08 (CH), 132.90 (CH), 141.59 (C), 144.65 (C), 152.20 (C),
153.91 (C), 172.90 (C).
HRMS (ESI): m/z [M + H]+ calcd for C30H35N2O5: 503.2546; found:
503.2552.
2-tert-Butyl 12a-Methyl (E,4aS,12aR)-1,2,3,4,4a,5,12,12a-Oc-
tahydro-9-(2-phenylvinyl)pyrido[3,4-b]acridine-2,12a-dicar-
boxylate (13c)
A soln of 8b (50 mg, 105 mmol), styrene (23 mg, 220 mmol, 2
equiv), cataCXium C (1.0 mg, 1.1 mmol, 1 mol%), and Et3N (43 mg,
430 mmol, 4 equiv) in DMF (1 mL) was heated under N2 to 100 °C
for 18 h. Subsequently, all volatile materials were removed under
high vacuum and the residue was suspended in CH2Cl2 (5 mL) and
washed with H2O (2 × 3 mL). The organic phase was dried
(MgSO4) and filtered and the solvent was evaporated. The residue
was chromatographed (silica gel, PE–EtOAc, 1:1, Rf = 0.38) to give
product 13c (42 mg, 80%) as a colorless solid; mp 200–205 °C
(dec).
HRMS (CI, isobutane): m/z [M + H]+ calcd for C29H40N3O4:
494.3019; found: 494.3018.
2-tert-Butyl 12a-Methyl (4aS,12aR)-9-Cyano-
1,2,3,4,4a,5,12,12a-octahydropyrido[3,4-b]acridine-2,12a-di-
carboxylate (13e)
A mixture of 8b (150 mg, 320 mmol), anhyd K4[Fe(CN)6] (24 mg,
64 mmol, 0.2 equiv), CuI (6 mg, 32 mmol, 0.1 equiv), N-butyl-1H-
imidazole (80 mg, 640 mmol, 2 equiv), and toluene (0.5 mL) was
heated at 160 °C for 16 h under an inert atmosphere in a tightly
closed reaction flask. The mixture was cooled to r.t., CH2Cl2 (5 mL)
was added, and the mixture was washed with H2O (3 × 5 mL). The
combined organic phases were dried (MgSO4) and filtered, the sol-
vent was evaporated, and the residue was chromatographed (silica
gel, PE–EtOAc, 1:1, Rf = 0.26) to give 13e (29 mg, 22%) as a green
resin.
[a]D20 +170 (c 1.0, CH2Cl2).
IR (ATR): 2976 (w), 2951 (w), 2925 (w), 2858 (w), 1728 (s), 1687
(vs), 1426 (vs), 1365 (m), 1240 (s), 1165 (vs), 1128 (s), 971 (m),
908 (m), 823 (m), 731 (s) cm–1.
1H NMR (500 MHz, CDCl3): d = 1.46 (s, 9 H), 1.60–1.73 (m, 1 H),
2.04–2.12 (m, 1 H), 2.13–2.30 (m, 1 H), 2.58–2.94 (m, 2 H), 2.75
Synthesis 2008, No. 14, 2199–2210 © Thieme Stuttgart · New York

PAPER
New Octahydropyrido[3,4-b]acridine Scaffolds for Combinatorial Chemistry
2205
[a]D20 +174 (c 1.8, CH2Cl2).
matography (silica gel, PE–EtOAc, 3:1, Rf = 0.28) gave 13g (106
mg, 93%) as a colorless solid; mp 98 °C.
[a]D20 +1.3 (c 5.5, CH2Cl2).
IR (ATR): 2955 (w), 2924 (m), 2226 (w), 1730 (m), 1691 (s), 1426
(s), 1277 (m), 1165 (s) cm–1.
1H NMR (500 MHz, CDCl3): d = 1.47 (s, 9 H) 1.64–1.96 (m, 1 H),
2.06–2.16 (m, 1 H), 2.16–2.32 (m, 1 H), 2.60–2.96 (m, 2 H), 2.78
(d, J = 16.3 Hz, 1 H), 3.23 (dd, J = 6.1 Hz, J = 18.6 Hz, 1 H), 3.30
(dd, J = 12.0 Hz, J = 18.6 Hz, 1 H), 3.38–3.50 (m, 1 H), 3.55 (s, 3
H), 4.20–4.50 (m, 1 H), 4.58–4.82 (m, 1 H), 7.75 (dd, J = 1.5 Hz,
J = 8.8 Hz, 1 H), 7.89 (s, 1 H), 8.03 (d, J = 8.8 Hz, 1 H), 8.12 (s, 1
H).
13C{1H} NMR (125 MHz, CDCl3): d = 28.04 (CH2), 28.35 (3 CH3),
37.19 (CH2), 37.86 (CH2), 39.95 (CH), 43.66 (0.5 CH2), 44.92 (0.5
CH2), 45.47 (C), 51.93 (CH3), 52.42 (0.5 CH2), 53.20 (0.5 CH2),
79.77 (C), 109.46 (C, C-CN), 118.73 (CN), 126.23 (C), 129.59
(CH), 129.87 (CH), 129.88 (C), 133.34 (CH), 135.37 (CH), 147.68
(C), 154.26 (C), 161.24 (C), 172.75 (C).
IR (ATR): 29.30 (w), 2862 (w), 1729 (m), 1690 (s), 1616 (w), 1426
(s), 1323 (vs), 1278 (m), 1240 (m), 1160 (s), 1110 (s), 1065 (m),
1017 (m), 840 (m), 765 (m) cm–1.
1H NMR (500 MHz, CDCl3): d = 1.46 (s, 9 H), 1.53–1.67 (m, 1 H),
2.01–2.09 (m, 1 H), 2.11–2.44 (m, 1 H), 2.56–2.93 (m, 2 H), 2.75
(d, J = 16.1 Hz, 1 H), 3.07–3.25 (m, 2 H), 3.37–3.48 (m, 1 H), 3.54
(s, 3 H), 4.17–4.46 (m, 1 H), 4.56–4.77 (m, 1 H), 7.48–7.54 (m, 1
H), 7.65 (d, J = 7.0 Hz, 1 H), 7.68–7.72 (m, 2 H), 7.74 (d, J = 8.1
Hz, 1 H), 7.84–7.89 (m, 3 H).
13C{1H} NMR (125 MHz, CDCl3): d = 28.02 (CH2), 28.35 (3 CH3),
37.12 (CH2), 37.89 (CH2), 40.18 (CH), 43.68 (0.5 CH2), 44.94 (0.5
CH2), 45.61 (C), 51.77 (CH3), 52.59 (0.5 CH2), 53.38 (0.5 CH2),
3
1
79.62 (C), 124.48 (q, J = 3.6 Hz, 2 CH), 124.50 (q, J = 293 Hz,
CF3), 125.50 (CH), 127.45 (C), 127.55 (CH), 128.94 (q, 2J = 32 Hz,
C), 129.70 (CH), 131.14 (2 CH, C), 135.31 (CH), 138.07 (C),
143.11 (C), 144.27 (C), 154.35 (C), 157.59 (C), 172.99 (C).
HRMS (CI, isobutane): m/z [M + H]+ calcd for C24H28N3O4:
422.2080; found: 422.2080.
2-tert-Butyl 12a-Methyl (4aS,12aR)-3,4,4a,5,12,12a-Octahydro-
7-phenylpyrido[3,4-b]acridine-2,12a-dicarboxylate (13f)
Following general procedure A using 8c (100 mg, 210 mmol),
PhB(OH)2 (30 mg, 230 mmol, 1.1 equiv), 10% Pd-C (5 mg, 4.7
mmol, 2.2 mol%), and K2CO3 (87 mg, 630 mmol, 3 equiv). Chroma-
tography (silica gel, PE–EtOAc, 1:3, Rf = 0.55) gave 13f (71 mg
71%) as a colorless solid; mp 89 °C.
HRMS (CI): m/z [M + H]+ calcd for C30H32F3N2O4: 541.2314;
found: 541.2315.
2-tert-Butyl 12a-Methyl (4aS,12aR)-1,2,3,4,4a,5,12,12a-Octahy-
dro-7-(phenylethynyl)pyrido[3,4-b]acridine-2,12a-dicarboxy-
late (13h)
A suspension of 8c (50 mg, 105 mmol), PhC≡CH (13 mg, 125 mmol,
1.2 equiv), Na2PdCl4 (0.5 mg, 1.7 mmol, 1.6 mol%), CataCXium
FBu (1.2 mg, 2.4 mmol, 2.3 mol%), and CuI (0.5 mg, 2.6 mmol, 2.6
mol%), in abs i-Pr2NH (1 mL) was heated under an inert atmosphere
to 100 °C for 16 h. All volatile materials were removed in vacuo and
CH2Cl2 (5 mL) was added. The mixture was washed with H2O
(2 × 3 mL) and the organic phase was dried (MgSO4). The mixture
was filtered, the solvent was evaporated, and the residue chromato-
graphed (silica gel, PE–EtOAc, 2:1, Rf = 0.39) to give 13h (27 mg,
51%) as a yellow-brown solid; mp 87 °C.
Alternative procedure: A mixture of 8c (50 mg, 105 mmol),
PhB(OH)2 (14 mg, 115 mmol, 1.1 equiv), Na2PdCl4 (0.4 mg, 1.4
mmol, 1.3 mol%), cataCXium FSulf (1.1 mg, 1.5 mmol, 1.5 mol%),
and K2CO3 (45 mg, 315 mmol, 3 equiv) was placed in a Schlenk
tube, evacuated, and flushed with N2 (2 ×). Degassed H2O (0.5 mL)
and BuOH (0.5 mL) were added and the resulting mixture stirred at
100 °C for 16 h. The mixture was cooled to r.t., the organic phase
was separated, and the aqueous phase extracted with CH2Cl2 (1 × 5
mL). The combined organic phases were dried (MgSO4) and fil-
tered, the solvents were evaporated, and the residue was chromato-
graphed (silica gel) to give 13f (35 mg, 71%).
[a]D20 –47.3 (c 1.1, CH2Cl2).
IR (ATR): 2976 (w), 2942 (w), 2859 (w), 1730 (s), 1693 (s), 1427
(s), 1365 (m), 1275 (m), 1166 (s), 758 (m), 731 (m) cm–1.
[a]D20 –2.3 (c 0.9, CH2Cl2).
IR (ATR): 2976 (w), 2951 (w), 2928 (w), 2860 (w), 1729 (m), 1684
(s), 1426 (s), 1240 (m), 1162 (s), 909 (m), 759 (m), 729 (s), 697 (m)
cm–1.
1H NMR (500 MHz, CDCl3): d = 1.45 (s, 9 H), 1.56–1.68 (m, 1 H),
2.00–2.08 (m, 1 H), 2.12–2.24 (m, 1 H), 2.57–2.92 (m, 2 H), 2.74
(d, J = 16.1 Hz, 1 H), 3.16–3.22 (m, 2 H), 3.36–3.49 (m, 1 H), 3.53
(s, 3 H), 4.17–4.46 (m, 1 H), 4.54–4.74 (m, 1 H), 7.36–7.42 (m, 1
H), 7.42–7.54 (m, 3 H), 7.66 (d, J = 7.1 Hz, 1 H), 7.69 (d, J = 8.1
Hz, 1 H), 7.75 (d, J = 7.1 Hz, 2 H), 7.86 (s, 1 H).
13C{1H} NMR (125 MHz, CDCl3): d = 28.04 (CH2), 28.37 (3 CH3),
37.10 (CH2), 37.93 (CH2), 40.20 (CH), 43.74 (0.5 CH2), 45.07 (0.5
CH2), 45.66 (C), 51.77 (CH3), 52.69 (0.5 CH2), 53.49 (0.5 CH2),
79.58 (C), 125.55 (CH), 126.70 (CH), 127.07 (CH), 127.45 (2 C),
127.65 (2 CH), 129.64 (CH), 130.92 (2 CH), 135.29 (CH), 139.44
(2 C), 144.47 (C), 154.34 (C), 157.17 (C), 173.01 (C).
1H NMR (500 MHz, CDCl3): d = 1.45 (s, 9 H), 1.58–1.70 (m, 1 H),
2.00–2.09 (m, 1 H), 2.16–2.32 (m, 1 H), 2.65–2.93 (m, 2 H), 2.68
(d, J = 16.0 Hz, 1 H), 3.25–3.31 (m, 2 H), 3.32–3.46 (m, 1 H), 3.52
(s, 3 H), 4.19–4.41 (m, 1 H), 4.51–4.75 (m, 1 H), 7.31–7.42 (m, 4
H), 7.62–7.68 (m, 3 H), 7.78 (br s, 1 H), 7.87 (dd, J = 1.1 Hz, J = 7.1
Hz, 1 H).
13C{1H} NMR (125 MHz, CDCl3): d = 28.02 (CH2), 28.36 (3 CH3),
37.26 (CH2), 37.84 (CH2), 40.09 (CH), 43.69 (0.5 CH2), 44.98 (0.5
CH2), 45.46 (C), 51.81 (CH3), 52.43 (0.5 CH2), 53.33 (0.5 CH2),
79.58 (C), 87.53 (C), 95.14 (C), 122.29 (C), 123.72 (C), 125.25
(CH), 127.00 (C), 127.61 (CH), 128.20 (3 CH, 1 C), 131.87 (2 CH),
133.25 (CH), 135.45 (CH), 146.70 (C), 154.02 (C), 158.41 (C),
172.91 (C).
HRMS (ESI): m/z [M + H]+ calcd for C31H33N2O4: 497.2440; found:
497.2445.
HRMS (CI, isobutane): m/z [M + H]+ calcd for C29H33N2O4:
473.2440; found: 473.2439.
2-tert-Butyl 12a-Methyl (4aS,12aR)-1,2,3,4,4a,5,12,12a-Octahy-
dro-7-(phenylamino)pyrido[3,4-b]acridine-2,12a-dicarboxy-
late (13i)
A suspension of Pd(OAc)2 (5 mg, 22 mmol, 5 mol%) and rac-
BINAP (20 mg, 32 mmol, 7.0 mol%) in abs toluene (2 mL) were
stirred for 5 min under an inert atmosphere. Compound 8c (200 mg,
421 mmol), PhNH2 (47 mg, 505 mmol, 1.2 equiv) and NaOt-Bu (66.1
mg, 688 mmol, 1.6 equiv) were added and the resulting mixture
stirred at 85 °C for 16 h. The mixture was cooled to r.t., CH2Cl2 (20
2-tert-Butyl 12a-Methyl (4aS,12aR)-1,2,3,4,4a,5,12,12a-Octahy-
dro-7-[4-(trifluoromethyl)phenyl]pyrido[3,4-b]acridine-2,12a-
dicarboxylate (13g)
Following general procedure A using 8c (100 mg, 210 mmol), 4-
F3CC6H4B(OH)2 (57 mg, 300 mmol, 1.4 equiv), 10% Pd-C (6 mg,
5.6 mmol, 2.7 mol%), and K2CO3 (88 mg, 630 mmol, 3 equiv). Chro-
Synthesis 2008, No. 14, 2199–2210 © Thieme Stuttgart · New York

2206
C. L. Diedrich et al.
PAPER
mL) was added, and the soln was washed with sat. aq NaHCO3 (10
mL). The organic phase was dried (MgSO4) and filtered, all volatile
materials were removed in vacuo, and the residue was chromato-
graphed (silica gel, PE–EtOAc, 3:1, Rf = 0.36) to give 13i (112 mg,
55%) as a yellow solid; mp 94 °C.
(MgSO4), filtered, and the solvent evaporated to give 14, generally
with high yields (>90%) and high purity (according to 1H NMR).
Methyl (4aS,12aR)-1,2,3,4,4a,5,12,12a-Octahydro-9-phenyl-
pyrido[3,4-b]acridine-12a-carboxylate (14a)
Following general procedure B using 13a (80 mg, 170 mmol) and
TFA (1.0 mL, 13.5 mmol) gave 14a (60 mg, 95%) as a pale yellow
solid; mp 170–175 °C (dec).
[a]D20 +124 (c 3.3, CH2Cl2).
[a]D20 –34 (c 0.95, CH2Cl2).
IR (ATR): 2976 (w), 2931 (w), 2861 (w), 1729 (m), 1692 (vs), 1568
m), 1520 (s), 1424 (s), 1381 (m), 1364 (m), 1240 (s), 1163 (vs),
1024 (m), 972 (m), 749 (vs) cm–1.
IR (ATR): 2948 (w), 2852 (w), 1721 (vs), 1485 (s), 1439 (m), 1222
(m), 1200 (s), 1177 (s), 1114 (m), 907 (w), 835 (m), 754 (s), 731 (s),
697 (m) cm–1.
1H NMR (500 MHz, CDCl3): d = 1.65–1.70 (m, 1 H), 1.87–1.98 (m,
1 H), 2.09 (ddd, J = 3.8 Hz, J = 7.5 Hz, J = 11.5 Hz, 1 H), 2.60 (d,
J = 12.9 Hz, 1 H), 2.74 (d, J = 16.9 Hz, 1 H), 2.80 (dd, J = 3.3 Hz,
J = 12.8 Hz, 1 H), 2.99 (br s, 1 H), 3.11–3.18 (m, 2 H), 3.25 (d,
J = 16.3 Hz, 2 H), 3.51–3.56 (m, 4 H), 7.36 (t, J = 7.3 Hz, 1 H), 7.46
(t, J = 7.5 Hz, 2 H), 7.67 (d, J = 7.3 Hz, 2 H), 7.81 (s, 1 H), 7.85–
7.89 (m, 2 H), 8.01 (d, J = 8.5 Hz, 1 H).
13C{1H} NMR (125 MHz, CDCl3): d = 29.22 (CH2), 37.56 (CH2),
38.14 (CH2), 39.95 (CH), 45.74 (C), 46.45 (CH2), 51.73 (CH3),
55.95 (CH2), 124.60 (CH), 127.17 (C), 127.27 (2 CH),127.50 (CH),
128.52 (CH), 128.76 (1 C, 1 CH), 128.86 (2 CH), 134.98 (CH),
138.42 (C), 140.46 (C), 146.14 (C), 157.74 (C), 174.39 (C).
1H NMR (500 MHz, CDCl3): d = 1.46 (s, 9 H), 1.60–1.74 (m, 1 H),
2.02–2.11 (m, 1 H), 2.14–2.36 (m, 1 H), 2.57–2.95 (m, 2 H), 2.74
(d, J = 16.0 Hz, 1 H), 3.15–3.32 (m, 2 H), 3.33–3.48 (m, 1 H), 3.53
(s, 3 H), 4.20–4.47 (m, 1 H), 4.66–4.78 (m, 1 H), 6.98–7.04 (m, 1
H), 7.09 (d, J = 8.0 Hz, 1 H), 7.28 (t, J = 8.0 Hz, 1 H), 7.32–7.40 (m,
5 H), 7.77 (s, 1 H), 8.20 (s, 1 H).
13C{1H} NMR (125 MHz, CDCl3): d = 28.12 (CH2), 28.35 (3 CH3),
36.75 (CH2), 37.82 (CH2), 40.09 (CH), 43.87 (0.5 CH2), 45.01 (0.5
CH2), 45.66 (C), 51.72 (CH3), 52.55 (0.5 CH2), 53.36 (0.5 CH2),
79.57 (C), 107.08 (CH), 115.82 (CH), 119.85 (2 CH), 121.84 (CH),
126.32 (CH), 127.35 (C), 128.12 (C), 129.25 (2 CH), 135.30 (CH),
137.23 (C), 139.36 (C), 141.96 (C), 154.17 (C), 154.62 (C), 172.90
(C).
HRMS (CI, isobutane): m/z [M + H]+ calcd for C29H34N3O4:
488.2549; found: 488.2551.
HRMS (EI): m/z [M]+ calcd for C24H24N2O2: 372.1838; found:
2-tert-Butyl 12a-Methyl (4aS,12aR)-7-Cyano-
372.1836.
1,2,3,4,4a,5,12,12a-octahydropyrido[3,4-b]acridine-2,12a-di-
carboxylate (13j)
Methyl (4aS,12aR)-1,2,3,4,4a,5,12,12a-Octahydro-9-(4-meth-
oxyphenyl)pyrido[3,4-b]acridine-12a-carboxylate (14b)
Following general procedure B using 13b (88 mg, 175 mmol) and
TFA (1.0 mL, 13.5 mmol) gave 14b (65 mg, 93%) as a pale yellow
solid; mp 180–185 °C (dec).
A suspension of 8c (150 mg, 320 mmol), dry K4[Fe(CN)6] (24 mg,
64 mmol, 0.2 equiv), CuI (6 mg, 32 mmol, 0.1 equiv), and N-butyl-
1H-imidazole (80 mg, 640 mmol, 2 equiv) in abs toluene (0.5 mL)
was heated under inert atmosphere to 160 °C for 16 h in a tightly
closed reaction flask. The mixture was cooled to r.t., CH2Cl2 (5 mL)
was added, and the mixture was washed with H2O (3 × 5 mL). The
organic phase was dried (MgSO4) and filtered and the solvent was
evaporated. The residue was chromatographed (silica gel, PE–
EtOAc, 1:3, Rf = 0.53) to give 13j (41 mg, 31%) as a green resin.
[a]D20 +152 (c 2.8, CH2Cl2).
IR (ATR): 2951 (w), 2835 (w), 1725 (s), 1608 (m), 1518 (s), 1489
(s), 1246 (vs), 1179 (vs), 1038 (m), 1020 (m), 824 (s), 731 (m), 669
(m) cm–1.
1H NMR (500 MHz, CDCl3): d = 1.62–1.68 (m, 1 H), 1.86–1.97 (m,
1 H), 2.05 (ddd, J = 4.0 Hz, J = 7.1 Hz, J = 11.8 Hz, 1 H), 2.57 (d,
J = 12.9 Hz, 1 H), 2.70–2.74 (m, 1 H), 2.71 (d, J = 16.0 Hz, 1 H),
2.78 (dd, J = 3.1 Hz, J = 12.7 Hz, 1 H), 3.13 (d, J = 16.3 Hz, 1 H),
3.14 (d, J = 1.8 Hz, 1 H), 3.18–3.25 (m, 1 H), 3.22 (d, J = 16.2 Hz,
1 H), 3.51 (d, J = 8.9 Hz, 1 H), 3.53 (s, 3 H), 3.83 (s, 3 H), 6.99 (d,
J = 8.8 Hz, 2 H), 7.60 (d, J = 8.8 Hz, 2 H), 7.76–7.80 (m, 2 H), 7.83
(dd, J = 2.0 Hz, J = 8.8 Hz, 1 H), 7.98 (d, J = 8.8 Hz, 1 H).
13C{1H} NMR (125 MHz, CDCl3): d = 29.30 (CH2), 37.54 (CH2),
38.13 (CH2), 39.97 (CH), 45.77 (C), 46.51 (CH2), 51.66 (CH3),
55.30 (CH3), 56.07 (CH2), 114.30 (2 CH), 123.73 (CH), 127.21 (C),
128.26 (2 CH), 128.30 (CH), 128.65 (CH), 128.73 (C), 132.90 (C),
134.81 (CH), 137.97 (C), 145.86 (C), 157.42 (C), 159.31 (C),
174.41 (C).
[a]D20 +27 (c 2.1, CH2Cl2).
IR (ATR): 2976 (w), 2953 (w), 2929 (w), 2860 (w), 2227 (w), 1727
(s), 1687 (vs), 1426 (vs), 1240 (m), 1164 (vs), 768 (m), 731 (m)
cm–1.
1H NMR (500 MHz, CDCl3): d = 1.45 (s, 9 H), 1.62–1.73 (m, 1 H),
2.04–2.14 (m, 1 H), 2.14–2.28 (m, 1 H), 2.58–2.98 (m, 2 H), 2.76
(d, J = 16.2 Hz, 1 H), 3.25–3.36 (m, 2 H), 3.36–3.49 (m, 1 H), 3.53
(s, 3 H), 4.20–4.48 (m, 1 H), 4.56–4.76 (m, 1 H), 7.46–7.50 (m, 1
H), 7.87 (s, 1 H), 7.92 (dd, J = 1.1 Hz, J = 8.2 Hz, 1 H), 7.99 (dd,
J = 1.1 Hz, J = 7.2 Hz, 1 H).
13C{1H} NMR (125 MHz, CDCl3): d = 27.88 (CH2), 28.37 (3 CH3),
37.16 (CH2), 37.94 (CH2), 39.98 (CH), 43.50 (0.5 CH2), 44.75 (0.5
CH2), 45.44 (C), 51.93 (CH3), 52.35 (0.5 CH2), 53.23 (0.5 CH2),
79.72 (C), 112.19 (C, C-CN), 117.45 (CN), 124.93 (CH), 126.85
(C), 132.02 (CH), 134.91 (CH), 135.29 (CH), 135.30 (C), 146.13
(C), 154.49 (C), 160.52 (C), 172.89 (C).
HRMS (EI): m/z [M]+ calcd for C25H26N2O3: 402.1943; found:
402.1942.
HRMS (CI, isobutane): m/z [M + H]+ calcd for C24H28N3O4:
422.2080; found: 422.2080.
Methyl (E,4aS,12aR)-1,2,3,4,4a,5,12,12a-Octahydro-9-(2-phe-
nylvinyl)pyrido[3,4-b]acridine-12a-carboxylate (14c)
Following general procedure B using 13c (100 mg, 200 mmol) and
TFA (1.0 mL, 13.5 mmol) gave 14c (77 mg, 97%) as a pale yellow
solid; mp 180–185 °C (dec).
Cleavage of the Boc Group; General Procedure B
Compound 13 (170 mmol) was added to cooled (ice-bath) TFA (1.0
mL, 13.5 mmol) and the resulting yellow mixture was stirred at r.t.
for 1 h. The mixture was cooled (ice bath) and 30% aq NaOH (10
mL) was slowly added. The resulting suspension was extracted with
CH2Cl2 (5 × 10 mL) and the combined organic phases were dried
[a]D20 +169 (c 1.8, CH2Cl2).
IR (ATR): 2946 (w), 2855 (w), 1721 (vs), 1496 (m), 1445 (m), 1207
(s), 1186 (s), 1113 (m), 960 (m), 824 (m), 751 (m), 694 (m) cm–1.
Synthesis 2008, No. 14, 2199–2210 © Thieme Stuttgart · New York

PAPER
New Octahydropyrido[3,4-b]acridine Scaffolds for Combinatorial Chemistry
2207
1H NMR (500 MHz, CDCl3): d = 1.63–1.69 (m, 1 H), 1.87–1.97 (m,
1 H), 2.00 (m, 2 H), 2.58 (d, J = 12.8 Hz, 1 H), 2.74 (d, J = 16.1 Hz,
1 H), 2.77 (dt, J = 2.8 Hz, J = 12.6 Hz, 1 H), 3.09–3.28 (m, 3 H),
3.25 (d, J = 16.5 Hz, 1 H), 3.53 (d, J = 12.4 Hz, 1 H), 3.55 (s, 3 H),
7.22 (d, J = 3.6 Hz, 2 H), 7.28 (t, J = 7.3 Hz, 1 H), 7.38 (t, J = 7.8
Hz, 2 H), 7.54 (d, J = 7.3 Hz, 2 H), 7.69 (s, 1 H), 7.76 (s, 1 H), 7.88
(dd, J = 1.7 Hz, J = 8.8 Hz, 1 H), 7.93 (d, J = 8.8 Hz, 1 H).
13C{1H} NMR (125 MHz, CDCl3): d = 29.53 (CH2), 37.67 (CH2),
38.23 (CH2), 40.15 (CH), 45.95 (C), 46.72 (CH2), 51.71 (CH3),
56.40 (CH2),125.26 (CH), 126.56 (3 CH), 127.30 (C), 127.84 (CH),
128.11 (CH), 128.75 (3 CH, 1 C), 128.98 (C), 129.55 (CH), 134.76
(CH), 137.15 (C), 146.62 (C), 157.71 (C), 174.54 (C).
2J = 32.2 Hz, C), 129.57 (CH), 131.15 (1 C, 2 CH), 134.89 (CH),
138.04 (C), 144.06 (C), 157.87 (C), 174.44 (C).
HRMS (CI, isobutane): m/z [M + H]+ calcd for C25H24F3N2O2:
441.1790; found: 441.1791.
Methyl (4aS,12aR)-1,2,3,4,4a,5,12,12a-Octahydro-7-(phenyl-
ethynyl)pyrido[3,4-b]acridine-12a-carboxylate (14f)
Following general procedure B using 13h (60 mg, 120 mmol) and
TFA (1.0 mL, 13.5 mmol) gave 14f (42 mg, 88%) as a colorless sol-
id; mp 150–155 °C (dec).
[a]D20 +165 (c 0.5, CH2Cl2).
IR (ATR): 2950 (m), 2857 (w), 1729 (vs), 1493 (m), 1444 (s), 1202
(vs), 1179 (s), 1116 (m), 913 (m), 760 (s), 732 (m), 695 (m) cm–1.
HRMS (CI, isobutane): m/z [M + H]+ calcd for C26H27N2O2:
399.2073; found: 399.2075.
1H NMR (500 MHz, CDCl3): d = 1.65–1.70 (m, 1 H), 1.89–198 (m,
1 H), 2.05–2.14 (m, 1 H), 2.57–2.63 (m, 1 H), 2.60 (d, J = 13.0 Hz,
1 H), 2.72 (d, J = 16.4 Hz, 1 H), 2.79 (dt, J = 3.2 Hz, J = 12.8 Hz, 1
H), 3.20–3.31 (m, 4 H), 3.50 (d, J = 12.8 Hz, 1 H), 3.55 (s, 3 H),
7.32–7.44 (m, 4 H), 7.66 (m, 3 H), 7.79 (s, 1 H), 7.89 (dd, J = 1.3
Hz, J = 7.1 Hz, 1 H).
Methyl (4aS,12aR)-9-(Cyclohexylamino)-1,2,3,4,4a,5,12,12a-
octahydropyrido[3,4-b]acridine-12a-carboxylate (14d)
Following general procedure B using 13d (110 mg, 223 mmol) and
TFA (1.0 mL, 13.5 mmol) gave 14d (87 mg, 99%) as a pale green
resin.
13C{1H} NMR (125 MHz, CDCl3): d = 29.14 (CH2), 37.91 (CH2),
37.97 (CH2), 39.98 (CH), 45.65 (C), 46.46 (CH2), 51.79 (CH3),
55.93 (CH2), 87.60 (C), 95.09 (C), 122.26 (C), 123.73 (C), 125.20
(CH), 127.08 (C), 127.59 (CH), 128.18 (CH), 128.20 (2 CH),
129.23 (C), 131.87 (2 CH), 133.17 (CH), 135.17 (CH), 146.53 (C),
158.68 (C), 174.50 (C).
[a]D20 +118 (c 1.5, CH2Cl2).
IR (ATR): 2929 (s), 2852 (m), 1721 (m), 1624 (vs), 1514 (m), 1448
(m), 1384 (s), 1248 (m), 1222 (m), 1203 (m), 1175 (m), 1147 (m),
1112 (m), 821 (s), 731 (m) cm–1.
1H NMR (500 MHz, CDCl3): d = 1.15–1.30 (m, 4 H), 1.35–1.46 (m,
2 H), 1.66 (t, J = 11.8 Hz, 2 H), 1.78 (d, J = 12.0 Hz, 2 H), 1.86–
1.98 (m, 1 H), 2.00–2.15 (m, 3 H), 2.58 (d, J = 12.9 Hz, 1 H), 2.68
(d, J = 16.1 Hz, 1 H), 2.77 (t, J = 12.7 Hz, 1 H), 3.04 (s, 1 H), 3.06
(d, J = 4.6 Hz, 1 H), 3.17 (d, J = 16.1 Hz, 1 H), 3.24 (dd, J = 3.0 Hz,
J = 12.8 Hz, 1 H), 3.30–3.39 (m, 1 H), 3.50 (d, J = 13.0 Hz, 1 H),
3.53 (s, 3 H), 3.75 (br s, 1 H), 6.59 (d, J = 2.1 Hz, 1 H), 6.96 (dd,
J = 2.4 Hz, J = 8.9 Hz, 1 H), 7.54 (s, 1 H), 7.71 (d, J = 9.0 Hz, 1 H).
13C{1H} NMR (125 MHz, CDCl3): d = 24.89 (CH2), 24.92 (CH2),
25.82 (CH2), 29.25 (CH2), 33.05 (CH2), 33.14 (CH2), 37.06 (CH2),
38.11 (CH2), 40.02 (CH), 45.78 (C), 46.49 (CH2), 51.56 (CH3),
51.70 (CH), 56.05 (CH2), 102.49 (CH), 121.06 (CH), 128.28 (C),
128.74 (C), 129.15 (CH), 132.54 (CH), 141.43 (C), 144.61 (C),
152.59 (C), 174.49 (C).
HRMS (CI, isobutane): m/z [M + H]+ calcd for C26H25N2O2:
397.1916; found: 397.1916.
Amide Formation; General Procedure C
A mixture of compound 14 (200 mmol, 1 equiv), amino or benzoic
acid (220 mmol, 1.1 equiv), DCC (220 mmol, 1.1 equiv), and HOBt
(220 mmol, 1.1 equiv) in CH2Cl2 (0.3 mL) was stirred at 23 °C for
16 h. It was then filtered through a pad of cotton, which was washed
with CH2Cl2 (0.5 mL). The filtrate was evaporated and its residue
chromatographed (silica gel).
Methyl (4aS,12aR)-2-(3-{[(9H-Fluoren-9-ylmethoxy)carbon-
yl]amino}propanoyl)-1,2,3,4,4a,5,12,12a-octahydropyrido-9-
phenylpyrido[3,4-b]acridine-12a-carboxylate (7a)
Following general procedure C using 14a (60 mg, 160 mmol),
Fmoc-b-alanine (56 mg, 180 mmol), DCC (37 mg, 180 mmol), and
HOBt (24 mg, 180 mmol) in CH2Cl2 (0.3 mL). Chromatography (sil-
ica gel, EtOAc, Rf = 0.17) gave 7a (102 mg, 95%) as a colorless sol-
id; mp 92 °C;NMR spectra list the signals of the main rotamer.
HRMS (CI, isobutane): m/z [M + H]+ calcd for C24H32N3O2:
394.2495; found: 394.2495.
Methyl (4aS,12aR)-1,2,3,4,4a,5,12,12a-Octahydro-7-[4-(trifluo-
romethyl)phenyl]pyrido[3,4-b]acridine-12a-carboxylate (14e)
Following general procedure B using 13g (105 mg, 194 mmol) and
TFA (1.0 mL, 13.5 mmol) gave 14e (62 mg, 73%) as a colorless sol-
id; mp 141 °C.
[a]D20 +75 (c 2.9, CH2Cl2).
IR (ATR): 3321 (w), 2931 (w), 2853 (w), 1720 (s), 1627 (vs), 1579
(m), 1441 (s), 1229 (vs), 1107 (m), 1089 (m), 1030 (m), 759 (m),
728 (s), 699 (m), 646 (m) cm–1.
[a]D20 +30 (c 3.0, CH2Cl2).
IR (ATR): 2950 (w), 2853 (w), 1728 (m), 1615 (w), 1434 (w), 1417
(w), 1324 (vs), 1164 (m), 1120 (s), 1066 (m), 769 (m) cm–1.
1H NMR (500 MHz, CDCl3): d = 1.71–1.83 (m, 1 H), 2.09–2.18 (m,
1 H), 2.25–2.36 (m, 1 H), 2.52 (d, J = 13.2 Hz, 1 H), 2.54–2.69 (m,
2 H), 2.72–2.91 (m, 1 H), 3.11–3.37 (m, 3 H), 3.43–3.48 (m, 3 H),
3.48–3.55 (m, 2 H), 3.98 (d, J = 13.0 Hz, 1 H), 4.18 (q, J = 6.4 Hz,
J = 12.7 Hz, 1 H), 4.32–4.39 (m, 2 H), 4.85 (d, J = 12.7 Hz, 1 H),
5.12 (d, J = 13.0 Hz, 1 H), 5.59–5.64 (m, 1 H), 7.26–7.31 (m, 2 H),
7.34–7.41 (m, 3 H), 7.48 (t, J = 7.7 Hz, 2 H), 7.56–7.60 (m, 2 H),
7.68 (d, J = 8.1 Hz, 2 H), 7.71–7.75 (m, 2 H), 7.81–7.85 (m, 1 H),
7.86–7.92 (m, 2 H), 8.00–8.05 (m, 1 H).
13C{1H} NMR (125 MHz, CDCl3): d = 28.44 (CH2), 33.00 (CH2),
36.72 (CH2), 36.81 (CH2), 37.71 (CH2), 40.12 (CH), 45.59 (C),
46.13 (CH2), 47.19 (CH), 50.79 (CH2), 51.98 (CH3), 66.57 (CH2),
119.87 (2 CH), 124.65 (CH), 125.04 (2 CH),126.96 (3 CH), 127.14
(C), 127.27 (2 CH), 127.58 (3 CH), 128.79 (CH), 128.89 (2 CH),
135.44 (CH), 138.63 (C), 140.35 (C), 141.21 (2 C), 143.92 (2 C),
1H NMR (500 MHz, CDCl3): d = 1.60–1.66 (m, 1 H), 1.85–1.96 (m,
1 H), 2.06 (ddd, J = 4.0 Hz, J = 7.3 Hz, J = 11.6 Hz, 1 H), 2.60 (d,
J = 12.9 Hz, 1 H), 2.70–2.73 (m, 1 H), 2.74 (d, J = 16.0 Hz, 1 H),
2.77 (dt, J = 3.2 Hz, J = 12.8 Hz, 1 H), 3.08 (d, J = 2.7 Hz, 1 H),
3.10 (d, J = 7.3 Hz, 1 H), 3.21–3.26 (m, 1 H), 3.28 (d, J = 16.5 Hz,
1 H), 3.54 (d, J = 13.4 Hz, 1 H), 3.56 (s, 3 H), 7.50 (dd, J = 7.3 Hz,
J = 8.0 Hz, 1 H), 7.65 (dd, J = 1.4 Hz, J = 7.1 Hz, 1 H), 7.69–7.71
(m, 2 H), 7.73 (dd, J = 1.3 Hz, J = 8.2 Hz, 1 H), 7.83 (s, 1 H), 7.86–
7.89 (m, 2 H).
13C{1H} NMR (125 MHz, CDCl3): d = 29.13 (CH2), 37.71 (CH2),
38.00 (CH2), 40.03 (CH), 45.76 (C), 46.47 (CH2), 51.72 (CH3),
3
1
55.97 (CH2), 124.49 (q, J = 3.5 Hz, 2 CH), 124.49 (q, J = 272.2
Hz, CF3), 125.42 (C), 127.51 (2 CH), 128.54 (C), 128.92 (q,
Synthesis 2008, No. 14, 2199–2210 © Thieme Stuttgart · New York

2208
C. L. Diedrich et al.
PAPER
146.31 (C), 156.41 (C), 156.22 (C), 170.10 (C), 172.68 (C), 172.83
(C).
HRMS (ESI): m/z [M + Na]+ calcd for C33H30N2NaO3: 525.2154;
found: 525.2146.
HRMS (ESI): m/z [M + H]+ calcd for C42H40N3O5: 666.2968; found:
666.2969.
Methyl (4aS,12aR)-9-(Cyclohexylamino)-1,2,3,4,4a,5,12,12a-
octahydro-2-(4-methoxybenzoyl)pyrido[3,4-b]acridine-12a-
carboxylate (7d)
Following general procedure C using 14d (82 mg, 210 mmol), 4-
MeOC6H4CO2H (32 mg, 0.21 mmol), DCC (48 mg, 230 mmol), and
HOBt (31 mg, 230 mmol) in CH2Cl2 (0.5 mL). Chromatography (sil-
ica gel, EtOAc–THF, 3:1, Rf = 0.43) gave 7d (106 mg, 97%) as a
colorless solid; mp 112 °C.
Methyl (4aS,12aR)-2-{2-[tert-Butoxycarbonyl)amino]-2-meth-
ylpropanoyl}-1,2,3,4,4a,5,12,12a-octahydro-9-(4-methoxyphe-
nyl)pyrido[3,4-b]acridine-12a-carboxylate (7b)
Following general procedure C using 14b (54 mg, 134 mmol), Boc-
Aib (30 mg, 148 mmol), DCC (30 mg, 145 mmol), and HOBt (20 mg,
146 mmmol) in CH2Cl2 (0.3 mL). Chromatography (silica gel,
EtOAc, Rf = 0.32) gave 7b (77 mg, 98%) as a colorless solid; mp
110 °C.
[a]D20 +84 (c 0.8, CH2Cl2).
IR (ATR): 2929 (w), 2853 (w), 1725 (m), 1621 (s), 1512 (m), 1431
(s), 1382 (m), 1247 (vs), 1173 (s), 1092 (m), 1026 (m), 838 (m), 595
(m) cm–1.
1H NMR (500 MHz, CDCl3): d = 1.13–1.31 (m, 4 H), 1.41 (dq,
J = 2.8 Hz, J = 12.2 Hz, 2 H), 1.64–1.72 (m, 2 H), 1.75–1.82 (m, 2
H), 2.06–2.19 (m, 3 H), 2.34 (br s, 1 H), 2.76 (d, J = 15.0 Hz, 2 H),
3.05 (br s, 1 H), 3.10–3.25 (m, 2 H), 3.31–3.41 (m, 2 H), 3.50 (s, 3
H), 3.83 (s, 3 H), 3.85–4.01 (m, 1 H), 5.09 (br s, 1 H), 6.59 (s, 1 H),
6.91 (d, J = 8.5 Hz, 2 H), 6.98 (d, J = 8.9 Hz, 1 H), 7.38 (d, J = 8.3
Hz, 2 H), 7.60 (s, 1 H), 7.76 (s, 1 H).
13C{1H} NMR (125 MHz, CDCl3): d = 24.89 (2 CH2), 25.82 (CH2),
28.4 (CH2), 33.01 (2 CH2), 33.12 (2 CH2), 36.20 (CH2), 37.87
(CH2), 40.27 (CH), 45.85 (C), 51.70 (CH3), 51.82 (CH), 55.26
(CH3), 102.38 (CH), 113.60 (2 CH), 121.45 (CH), 127.46 (C),
128.07 (C), 128.78 (2 CH, C), 128.97 (CH), 133.09 (CH), 141.45
(C), 144.79 (C), 151.83 (C), 160.62 (C), 170.47 (C), 172.69 (C).
[a]D20 +80 (c 2.0, CH2Cl2).
IR (ATR): 3317 (w), 2928 (m), 2850 (w), 1709 (s), 1625 (s), 1490
(s), 1437 (s), 1365 (m), 1244 (vs), 1157 (vs), 1070 (m), 1037 (m),
823 (s), 730 (s), 642 (m) cm–1.
1H NMR (500 MHz, CDCl3): d = 1.44 (s, 9 H), 1.48–1.59 (m, 6 H),
1.74 (d, J = 12.1 Hz, 1 H), 2.09–2.18 (m, 1 H), 2.26–2.38 (m, 1 H),
2.55 (d, J = 12.8 Hz, 1 H), 2.78 (d, J = 16.0 Hz, 1 H), 3.10 (t,
J = 12.4 Hz, 1 H), 3.20 (dd, J = 6.3 Hz, J = 18.1 Hz, 1 H), 3.26 (dd,
J = 12.5 Hz, J = 17.8 Hz, 1 H), 3.44–3.50 (m, 1 H), 3.51 (s, 3 H),
3.87 (s, 3 H), 4.66–4.77 (m, 1 H), 5.14–5.29 (m, 2 H), 7.02 (d,
J = 8.7 Hz, 2 H), 7.63 (d, J = 8.7 Hz, 2 H), 7.82–7.84 (m, 1 H),
7.85–7.88 (m, 2 H), 8.00 (d, J = 8.8 Hz, 1 H).
13C{1H} NMR (125 MHz, CDCl3): d = 26.15 (2 CH3), 28.31 (3
CH3), 28.56 (CH2), 36.65 (CH2), 38.01 (CH2), 40.21 (CH), 45.69
(C), 46.45 (CH2), 51.91 (CH3), 52.64 (CH2), 55.35 (CH3), 56.72
(C), 79.40 (C), 114.36 (2 CH), 123.83 (CH), 127.22 (C), 128.03 (C),
128.13 (2 CH), 128.60 (2 CH), 132.87 (C), 135.45 (CH), 138.17
(C), 146.04 (C), 157.72 (C), 156.90 (C), 159.39 (C), 171.81 (C),
172.62 (C).
HRMS (CI, isobutane): m/z [M + H]+ calcd for C32H38N3O4:
528.2862; found: 528.2862.
Methyl (4aS,12aR)-(2-(S)-2-{[(9H-Fluoren-9-ylmethoxy)carbo-
nyl]amino}-4,4-dimethylbutanoyl)-1,2,3,4,4a,5,12,12a-octahy-
dro-7-[4-(trifluoromethyl)phenyl]pyrido[3,4-b]acridine-12a-
carboxylate (7e)
HRMS (ESI): m/z [M + Na]+ calcd for C34H41N3NaO6: 610.2893;
found: 610.2900.
Following general procedure C using 14e (62 mg, 141 mmol), N-
Fmoc-L-neopentylglycine (57 mg, 155 mmol), DCC (32 mg, 155
mmol), and HOBt (20 mg, 146 mmmol) in CH2Cl2 (0.3 mL); the mix-
ture was stirred for 3 d. Chromatography (silica gel, PE–EtOAc,
1:1, Rf = 0.45) gave 7e (66 mg, 60%) as a colorless solid; mp
128 °C; NMR spectra list the signals of the main rotamer.
Methyl (E,4aS,12aR)-2-Benzoyl-1,2,3,4,4a,5,12,12a-octahydro-
9-(2-phenylvinyl)pyrido[3,4-b]acridine-12a-carboxylate (7c)
Following general procedure C using 14c (77 mg, 193 mmol),
PhCO2H (26 mg, 213 mmol), DCC (44 mg, 213 mmol), and HOBt
(29 mg, 213 mmol) in CH2Cl2 (0.5 mL). Chromatography (silica gel,
EtOAc, Rf = 0.33) gave 7c (94 mg, 97%) as a colorless solid; mp
191 °C.
[a]D20 –36 (c 2.7, CH2Cl2).
[a]D20 +178 (c 2.9, CH2Cl2).
IR (ATR): 3294 (w), 2951 (w), 2864 (w), 1722 (m), 1638 (m), 1511
(w), 1447 (m), 1323 (vs), 1226 (m), 1164 (m), 1121 (s), 1108
(m),1065 (m), 736 (s) cm–1.
IR (ATR): 3059 (w), 3024 (w), 2951 (w), 2909 (w), 1727 (s), 1630
(vs), 1600 (m), 1493 (m), 1433 (s), 1375 (m), 1326 (m), 1278 (m),
1259 (m), 1226 (m), 1195 (s), 1179 (m), 1145 (m), 1091 (m), 1025
(m), 966 (m), 827 (m), 783 (m), 747 (s), 731 (s), 695 (s), 631 (m)
cm–1.
1H NMR (500 MHz, CDCl3): d = 1.58–1.77 (m, 1 H), 2.11–2.43 (m,
1 H), 2.22–2.43 (m, 1 H), 2.63–2.85 (m, 2 H), 3.04–3.15 (m, 1 H),
3.20 (dd, J = 6.2 Hz, J = 18.2 Hz, 1 H), 3.27 (dd, J = 12.0 Hz,
J = 18.2 Hz, 1 H), 3.41–3.49 (m, 1 H), 3.55 (s, 3 H), 3.79–4.46 (m,
1 H), 4.82–5.36 (m, 1 H), 7.21 (s, 2 H), 7.26–7.30 (m, 1 H), 7.38 (t,
J = 7.6 Hz, 2 H), 7.40–7.43 (m, 5 H), 7.55 (d, J = 7.4 Hz, 2 H), 7.68
(s, 1 H), 7.88 (dd, J = 1.6 Hz, J = 8.9 Hz, 1 H), 7.76–7.86 (m, 1 H),
7.94 (d, J = 8.8 Hz, 1 H).
13C{1H} NMR (125 MHz, CDCl3): d = 28.50 (CH2), 36.74 (CH2),
37.85 (CH2), 40.17 (CH), 45.79 (C), 48.24 (CH2), 50.89 (CH2),
51.99 (CH3), 125.23 (CH), 126.56 (2 CH), 126.76 (CH), 126.82 (2
CH), 126.99 (C), 127.22 (C), 127.87 (CH), 127.92 (CH), 128.41 (2
CH), 128.60 (CH), 128.72 (2 CH), 129.91 (CH), 129.68 (CH),
134.92 (C), 135.24 (CH), 135.92 (C), 137.02 (C), 146.64 (C),
156.81 (C), 170. 55 (C), 172.56 (C).
1H NMR (500 MHz, CDCl3): d = 1.04 (s, 9 H), 1.47–1.54 (m, 1 H),
1.57–1.64 (m, 1 H), 1.77 (d, J = 12.3 Hz, 1 H), 2.08–2.19 (m, 1 H),
2.24–2.35 (m, 1 H), 2.54 (d, J = 13.2 Hz, 1 H), 2.80 (d, J = 16.1 Hz,
1 H), 3.11–3.28 (m, 3 H), 3.30–3.39 (m, 1 H), 3.51 (s, 3 H), 3.56 (s,
1 H), 4.15–4.34 (m, 2 H), 4.38–4.48 (m, 1 H), 4.78–4.95 (m, 1 H),
5.13 (d, J = 13.1 Hz, 1 H), 5.53 (d, J = 9.4 Hz, 1 H), 7.31 (t, J = 7.5
Hz, 2 H), 7.35–7.43 (m, 2 H), 7.50–7.54 (m, 1 H), 7.57–7.63 (m, 2
H), 7.67 (dd, J = 1.1 Hz, J = 7.1 Hz, 1 H), 7.71 (d, J = 8.2 Hz, 2 H),
7.73–7.78 (m, 3 H), 7.85–7.91 (m, 3 H).
13C{1H} NMR (125 MHz, CDCl3): d = 28.20 (CH2), 29.79 (3 CH3),
30.90 (C), 36.79 (CH2), 37.76 (CH2), 40.15 (CH), 45.54 (C), 45.95
(CH2), 46.71 (CH2), 47.21 (CH), 48.36 (CH), 50.88 (CH2), 51.90
(CH3), 66.97 (CH2), 119.92 (2 CH), 124.50 (q, 1J = 275.3 Hz, CF3),
124.54 (q, 3J = 3.6 Hz, 2 CH), 125.15 (2 CH), 125.64 (CH), 127.04
2
(2 CH), 127.47 (C), 127.64 (3 CH), 128.98 (q, J = 32.1 Hz, C),
129.80 (CH), 131.15 (2 CH), 135.45 (CH), 138.12 (C), 141.25 (2
C), 143.07 (C), 143.80 (2 C), 144.30 (C), 155.91 (C), 157.09 (C),
171.86 (C), 171.99 (C), 172.55 (C).
Synthesis 2008, No. 14, 2199–2210 © Thieme Stuttgart · New York

PAPER
New Octahydropyrido[3,4-b]acridine Scaffolds for Combinatorial Chemistry
2209
HRMS (ESI): m/z [M + Na]+ calcd for C47H46F3N3NaO5: 812.3287;
Exp. Ther. 2008, 324, 497. (d) Troxler, T.; Enz, A.; Hoyer,
found: 812.3214.
D.; Langenegger, D.; Neumann, P.; Pfäffli, P.; Schoeffter,
P.; Hurth, K. Bioorg. Med. Chem. Lett. 2008, 18, 979.
(e) Loza-Mejia, M. A.; Maldonado-Herandez, K.;
Rodriguez-Hernandez, F.; Rodriguez-Sotres, R.; Gonzales-
Sanchez, I.; Quintero, A.; Solano, J. D.; Lira-Rocha, A.
Bioorg. Med. Chem. 2008, 16, 1142. (f) Lavrado, J.; Paulo,
A.; Gut, J.; Rosenthal, P. J.; Moreira, R. Bioorg. Med. Chem.
Lett. 2008, 18, 1378. (g) Couch, G. D.; Burke, P. J.; Knox,
R. J.; Moody, C. J. Tetrahedron 2008, 64, 2816.
(h) Dalla Via, L.; Gia, O.; Gasparotto, V.; Ferlin, M. G. Eur.
J. Med. Chem. 2008, 43, 429. (i) Kinney, W. A.; Teleha, C.
A.; Thompson, A. S.; Newport, M.; Hansen, R.; Ballentine,
S.; Ghosh, S.; Mahan, A.; Grasa, G.; Zanotti-Gerosa, A.;
Dingenen, J.; Schubert, C.; Zhou, Y.; Leo, G. C.;
McComsey, D. F.; Santulli, R. J.; Maryanoff, B. E. J. Org.
Chem. 2008, 73, 2302.
Methyl (4aS,12aR)-1,2,3,4,4a,5,12,12a-Octahydro-2-(3-nitro-
benzoyl)-7-(phenylethynyl)pyrido[3,4-b]acridine-12a-carboxyl-
ate (7f)
A soln of 14f (52 mg, 130 mmol), 3-O2NC6H4COCl (27 mg, 140
mmol, 1.1 equiv), and Et3N (29 mg, 290 mmol, 2.2 equiv) in CH2Cl2
(2 mL) was stirred for 18 h. CH2Cl2 (10 mL) was added and the soln
washed with H2O (10 mL). The organic phase was dried (MgSO4)
and filtered and the solvent was evaporated. The residue chromato-
graphed (silica gel, EtOAc, Rf = 0.52) to give 7f as a brown solid (43
mg, 59%); mp 125 °C.
[a]D20 +30 (c 0.6, CH2Cl2).
IR (ATR): 2926 (w), 2866 (w), 2363 (w), 2326 (w), 2164 (w), 1725
(s), 1639 (vs), 1531 (vs), 1484 (s), 1442 (vs), 1350 (vs), 1275 (m),
1228 (m), 1203 (m), 1102 (m), 1028 (m), 759 (s), 724 (s), 693 (s)
cm–1.
1H NMR (500 MHz, CDCl3): d = 1.71 (br s, 1 H), 2.20–2.26 (m, 1
H), 2.32–2.47 (m, 1 H), 2.71–2.88 (m, 2 H), 3.03–3.35 (m, 2 H),
3.31 (dd, J = 12.5 Hz, J = 18.2 Hz, 1 H), 3.43 (dd, J = 4.4 Hz,
J = 18.4 Hz, 1 H), 3.57 (br s, 3 H), 3.75–3.88 (m, 1 H), 4.89–5.28
(m, 1 H), 7.30–7.49 (m, 4 H), 7.64 (t, J = 8.1 Hz, 1 H), 7.69 (dd,
J = 1.5 Hz, J = 7.9 Hz, 2 H), 7.70–7.81 (m, 2 H), 7.92 (d, J = 6.7 Hz,
2 H), 8.25–8.33 (m, 2 H).
13C{1H} NMR (125 MHz, CDCl3): d = 28.32 (CH2), 37.04 (CH2),
37.53 (CH2), 40.04 (CH), 45.61 (C), 48.23 (CH2), 50.67 (CH2),
52.18 (CH3), 87.45 (C), 95.26 (C), 121.98 (CH), 122.28 (C), 123.61
(C), 124.39 (CH), 125.45 (CH), 127.01 (C), 127.64 (CH), 128.25 (1
C, 2 CH), 128.28 (CH), 129.75 (CH), 131.85 (2 CH), 132.59 (CH),
133.43 (CH), 135.53 (CH), 137.60 (C), 146.64 (C), 148.03 (C),
157.76 (C), 167.93 (C), 172.48 (C).
(5) (a) Christoffers, J.; Scharl, H.; Frey, W.; Baro, A. Eur. J.
Org. Chem. 2004, 2701. (b) Christoffers, J.; Scharl, H.;
Frey, W.; Baro, A. Org. Lett. 2004, 6, 1171.
(c) Christoffers, J.; Scharl, H. Eur. J. Org. Chem. 2002,
1505.
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(8) Ashburn, B. O.; Rathbone, L. K.; Camp, E. H.; Carter, R. G.
Tetrahedron 2008, 64, 856.
(9) Li, A.-H.; Ahmed, E.; Chen, X.; Cox, M.; Crew, A. P.;
Dong, H.-Q.; Jin, M.; Ma, L.; Panicker, B.; Siu, K. W.;
Steinig, A. G.; Stolz, K. M.; Tavares, P. A. R.; Volk, B.;
Weng, Q.; Werner, D.; Mulvihill, M. J. Org. Biomol. Chem.
2007, 5, 61.
(10) Zhang, C.; De C, K.; Mal, R.; Seidel, D. J. Am. Chem. Soc.
2008, 130, 416.
HRMS (ESI): m/z [M + Na]+ calcd for C33H27N3NaO5: 568.1848;
found: 568.1831.
(11) CCDC-682901 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
at www.ccdc.cam.ac.uk/conts/retrieving.html [or from the
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44(1223)336033; e-mail:
deposit@ccdc.cam.ac.uk].
Acknowledgment
This work was generously supported by the Fonds der Chemischen
Industrie. Thanks to Dr. Renat Kadyrov, Evonik Degussa GmbH,
Hanau for providing us with catalysts and ligands.
(12) Review: Felpin, F.-X.; Ayad, T.; Mitra, S. Eur. J. Org.
Chem. 2006, 2679.
(13) cataCXium FSulf = dicyclohexyl{2-sulfo-9-[3-(4-sulfo-
phenyl)propyl]-9H-fluoren-9-yl}phosphonium hydrogen-
sulfate; cataCXium C = trans-bis(acetato)bis[2-(di-2-tolyl-
phosphino)benzyl]dipalladium(II); cataCXium PIntB = 2-
(di-tert-butylphosphino)-1-phenylindole, cataCXium FBu =
(9-butyl-9H-fluoren-9-yl)dicyclohexylphosphonium
tetrafluoroborate.
(14) (a) Fleckenstein, C. A.; Plenio, H. Green Chem. 2007, 9,
1287. (b) Fleckenstein, C. A.; Plenio, H. Chem. Eur. J. 2007,
13, 2701.
(15) (a) Meyer, F. E.; Ang, K. H.; Steinig, A. G.; de Meijere, A.
Synlett 1994, 191. (b) Ang, K. H.; Bräse, S.; Steinig, A. G.;
Meyer, F. E.; Llebaria, A.; Voigt, K.; de Meijere, A.
Tetrahedron 1996, 52, 11503. (c) Review: de Meijere, A.;
Meyer, F. E. Angew. Chem. Int. Ed. 1994, 33, 2379; Angew.
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C. L. Diedrich et al.
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