Synthesis of indolobenzazepinones by application of an isocyanide-based multicomponent reaction

Article abstract of DOI:10.1002/ejoc.200800643

Application of a Ugi multicomponent reaction to oxo acids 4 allows the formation of potentially antimitotic indolobenzazepinones of type 5 in good yields of up to 72%, whereas the same transformation from the starting substrate 6 gives access to analogues of paullone with yields of up to 89%. The reaction could be applied to a wide range of isocyanides, thereby ensuring introduction of molecular diversity at the key C-5 position. Use of cyclohexenyl isocyanide allows post-condensation modifications, while careful choice of the amine and the indole protecting groups proved to be important for providing the deprotected compounds necessary for biological tests. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800643

FULL PAPER
DOI: 10.1002/ejoc.200800643
Synthesis of Indolobenzazepinones by Application of an Isocyanide-Based
Multicomponent Reaction
Stéphane Beaumont,[a] Pascal Retailleau,[a] Philippe Dauban,*[a] and Robert H. Dodd*[a]
Keywords: Multicomponent reactions / Isocyanide / Intramolecular / Indoles / Azepines
Application of a Ugi multicomponent reaction to oxo acids 4
allows the formation of potentially antimitotic indolobenz-
azepinones of type 5 in good yields of up to 72%, whereas
the same transformation from the starting substrate 6 gives
access to analogues of paullone with yields of up to 89%.
The reaction could be applied to a wide range of isocyanides,
thereby ensuring introduction of molecular diversity at the
key C-5 position. Use of cyclohexenyl isocyanide allows post-
condensation modifications, while careful choice of the
amine and the indole protecting groups proved to be impor-
tant for providing the deprotected compounds necessary for
biological tests.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
C11N5 marine sponge bromo alkaloids represented by hy-
menialdisine (3).[9,10] We demonstrated that compounds of
type 1 display potent antimitotic properties in the micromo-
lar range as a consequence of tubulin polymerization inhibi-
tion.[11] In particular, it was found that the presence of an
alkyl side chain at the C-5 position is crucial in order to
obtain cytotoxic effects in the nanomolar range (Figure 1).
Introduction
Multicomponent reactions (MCRs) are convergent meth-
ods highly useful when the generation of molecular diver-
sity is needed, in the context of, for example, a structure/
activity relationship study.[1] In a single step, the combina-
tion of up to six starting materials can lead to the formation
of a wide variety of functionalized molecules through a cas-
cade of elementary steps. Of the various available protocols,
the isocyanide-based multicomponent reaction offers by far
the greatest synthetic potential in terms of diversity and
versatility, a consequence of the unique reactivity of this
function.[2] The well-known Ugi four-component reaction[3]
(4-CR) – involving sequential condensation between an
amine, a carbonyl compound, an isocyanide, and a carbox-
ylic acid – allows introduction of diversity through varia-
tion of the substitution pattern on each reagent. This trans-
formation has thus been successfully applied to the prepara-
tion of numerous heterocyclic scaffolds[4] that sometimes
display biological activities,[5] as well as of natural products
and their derivatives.[6] More interestingly, intramolecular
Ugi 4-CRs based on the use of bifunctional reagents such
as oxo acids or β-amino acids allow access to a wide range
of novel heterocycles.[7]
Figure 1. Structures of compounds 1–3.
This observation prompted us to screen various alkyl
substituents at C5, and it occurred to us that application of
an intramolecular Ugi 4-CR from a starting indole-derived
oxo acid of type 4 could offer new opportunities for gener-
ating molecular diversity at this position.[12] In particular,
In the context of a medicinal chemistry project directed
towards finding new antitumor agents, we were prompted
to prepare indolobenzazepinone derivatives of type 1, the
pyrrolo[2,3-c]azepinone core of which can be found in sev-
eral natural products such as latonduine (2)[8] and the
[a] Institut de Chimie des Substances Naturelles, UPR 2301
CNRS,
Avenue de la Terrasse, Bât. 27, 91198 Gif-sur-Yvette Cedex,
France
Fax: +33-1-69077247
E-mail: philippe.dauban@icsn.cnrs-gif.fr
robert.dodd@icsn.cnrs-gif.fr
Scheme 1. Intramolecular Ugi 4-CRs for the preparation of indolo-
benzazepinones of type 5 and 7.
5162
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5162–5175

Isocyanide-Based Multicomponent Reactions
such modifications should be possible through variation of served with indole derivatives 4a and 4c (Entries 1–13 and
the starting isocyanide, a large variety of which are com- 18–19), while the presence of a fluorine at C-5 (i.e., com-
mercially available (Scheme 1). We also envisaged that use pound 4b) slightly decreases the reactivity (Entries 14, 16,
of the isomeric oxo acid 6 should afford a different type of 17 vs. 8, 10, 12, respectively).
indolobenzazepinone 7, which can be regarded as ana-
logues of paullones 8, another class of heterocyclic products
that display potent antitumor properties.[13] We therefore
wish to describe here the application of an isocyanide-based
multicomponent reaction to the preparation of indolo-
benzazepinones of therapeutic interest.
Results and Discussion
Initial efforts were concentrated on the preparation of
starting oxo acids 4 with different substituents at the C-5
position in the indole nucleus. These were prepared in four
steps from the commercially available ethyl indole-2-carb-
oxylates 9 (Scheme 2). Iodination under basic conditions,
followed by protection of the indole nitrogen with ben-
zenesulfonyl chloride, afforded compounds 11 in good
yields.[14] Suzuki coupling of 11 with 2-formylbenzene-
boronic acid, catalyzed by Pd(OAc)2 (3 mol-%) in the pres-
ence of dppf (4.5 mol-%) and cesium fluoride (4 equiv.),[15]
thus led to the formation of biaryl derivatives 12 with yields
in the 79–92% range. Finally, concomitant saponification
and removal of the sulfonyl protecting group with LiOH
(1 ) gave the expected intermediates 4, which were used
without purification.
Figure 2. Amines and isocyanides used for intramolecular Ugi 4-
CRs.
Table 1. Intramolecular Ugi 4-CRs starting from oxo acid 4.
Entry R1NH2
R2NC
R3
Product Yield[a]
1
2
3
4
5
6
7
8
Bn: 13a
PMB: 13b
Me: 13c
iPr: 13d
Cy: 14a
H: 4a
H: 4a
H: 4a
H: 4a
H: 4a
H: 4a
H: 4a
H: 4a
H: 4a
H: 4a
H: 4a
H: 4a
H: 4a
F: 4b
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
5s
51
56
33
48
40
54
55
56
37
57
41
63
32
39
38
52
52
56
78
n-C4H9: 14b
morpholine: 14c
morpholine: 14c
morpholine: 14c
allyl: 13e
n-C5H11: 13f morpholine: 14c
tBu: 13g
tBu: 13g
tBu: 13g
tBu: 13g
tBu: 13g
tBu: 13g
tBu: 13g
tBu: 13g
tBu: 13g
tBu: 13g
tBu: 13g
tBu: 13g
tBu: 13g
n-C4H9: 14b
morpholine: 14c
ester: 14d
9
10
11
12
13
14
15
16
17
18
19
Bn: 14e
Me: 14f
tBu: 14g
cyclohexene: 14h
morpholine: 14c
ester: 14d
F: 4b
Bn: 14e
tBu: 14g
morpholine: 14c
tBu: 14g
F: 4b
F: 4b
BnO: 4c
BnO: 4c
Scheme 2. Synthesis of oxo acids 4. Reagents and conditions:
a) KOH (3.8 equiv.), I2 (1 equiv.), DMF, room temp., 45 min;
b) PhSO2Cl (2 equiv.), NaH (1.5 equiv.), THF, room temp., 16 h;
c) Pd(OAc)2 (3 mol-%), dppf (4.5 mol-%), CsF (4 equiv.), dioxane,
80 °C, 3–5 h; d) LiOH (1 , 5 equiv.), THF, 60 °C, 16 h.
[a] Isolated yields after flash chromatography on silica gel.
X-ray crystallography of racemic 5l allowed us to con-
Compounds 4a–c were engaged in intramolecular Ugi firm the structures of the indolobenzazepinones (Figure 3).
4-CRs – based on the optimized conditions developed by The reactions were found to occur either with benzyl-
Ivachtchenko et al. for the synthesis of thiazepines starting amines or a variety of linear (methyl, allyl, n-C5H11) and
from oxo acids[7b] – with a variety of isocyanides and pri- branched (iPr, tBu) alkylamines, while a wide range of sub-
mary amines (Figure 2). We were pleased to observe that stituted isocyanide components could be introduced with-
the reactions occur smoothly without any protecting group out diminishing the yields. More interestingly, the cyclohex-
on the indole moiety. The corresponding indolobenzazep- enyl analogue 5m allows postcondensation modifications at
inones 5a–s were thus isolated with moderate to good yields the C-5 position. Ugi was the first to prepare 1-isocyanocy-
in the 32–78% range (Table 1), the best results being ob- clohexene (14h), which was then used in a multicomponent
Eur. J. Org. Chem. 2008, 5162–5175
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5163

S. Beaumont, P. Retailleau, P. Dauban, R. H. Dodd
FULL PAPER
mitotic activity is concerned.[18] This can thus be fine-tuned
by modifications either of the starting amine or of the iso-
cyanide.
Scheme 4. Deprotection of tert-butyl lactams.
We then turned our attention to the synthesis of indolo-
benzazepinones of type 7, which may be regarded as iso-
meric analogues of paullones 8. Preparation of the required
oxo acid 6 started from the commercially available N-(Boc)-
indole-2-boronic acid (20, Scheme 5). Suzuki coupling with
methyl o-iodobenzoate afforded the 2-arylindole derivative
21 in an excellent yield of 97%. The N-Boc protecting
group was then removed under acidic conditions, before a
Vilsmeier–Haack formylation of 22 with POCl3 and N-
methylformanilide that efficiently led to the expected alde-
hyde 23.[19] The ester was finally saponified with aqueous
lithium hydroxide to give the target compound 6a in quanti-
tative yield.
Figure 3. X-ray structure of indolobenzazepinone 5l.
reaction.[16] The resulting cyclohexenamide could be depro-
tected under acidic conditions to afford the primary amide,
and Armstrong later extended the versatility of this isocya-
nide by describing conditions that led variously to acids,
esters, or thioesters.[17] In our hands, the cyclohexenamide
5m was efficiently transformed into the primary amide 15
by treatment with acetyl chloride in methanol, whereas
Swern oxidation of 15 provided the cyano derivative 16
(Scheme 3).
Scheme 5. Synthesis of oxo acids 6. Reagents and conditions:
a) methyl o-iodobenzoate (1 equiv.), Pd(PPh3)4 (5 mol-%), Na2CO3
(2 , 4.2 equiv.), DME, reflux, overnight; b) TFA (2 equiv.),
CH2Cl2, room temp., overnight; c) POCl3 (1.5 equiv.), N-methyl-
formanilide (1.5 equiv.), ClCH2CH2Cl, reflux; d) BnBr (2 equiv.),
NaH (1.5 equiv.), THF, room temp.; e) N,N-dimethylsulfamoyl
chloride (2 equiv.), NaH (1.5 equiv.), THF, room temp.; f) LiOH
(1 , 5 equiv.), THF, 60 °C, 16 h.
Scheme 3. Postcondensation modifications of 5m. Reagents and
conditions: a) AcCl (5 equiv.), CH3OH, room temp., 30 min;
b) DMSO (2.4 equiv.), oxalyl chloride (1.3 equiv.), Et3N (5 equiv.),
CH2Cl2, –78 °C, 4 h.
Finally, because the best biological activities observed in
our previous study had been with free 6-NH indolobenza-
zepinones of type 1,[11] use of tert-butylamine in the Ugi 4-
CR proved to be optimal, because it affords protected lac-
Contrarily to what had been observed with the formation
tams 5g–s, the deprotection of which occurs smoothly at of compounds 5, intramolecular Ugi 4-CRs with depro-
room temperature in the presence of trifluoroacetic acid tected indole substrates of type 6 did not occur efficiently.
and anisole in dichloromethane. As examples, the tert-butyl Treatment of compound 6a with tert-butylamine (13g) and
lactams 5g and 5h were transformed into products 17 and tert-butyl isocyanide (14g) thus afforded indolobenzazepi-
18 in 80% and 79% yields, respectively (Scheme 4). Surpris- none 7a in a very low yield of 8% even after 2 d in methanol
ingly, selective deprotection was observed in the case of di- at 50 °C (Entry 1, Table 2), while the same reagents with
tert-butyl compound 5q, to afford a quantitative yield of substrate 4a had led to indolobenzazepinone 5l in a good
the mono-tert-butyl amide 19. However, application of the yield of 63% (Entry 12, Table 1). Changing solvents (THF,
Ugi 4-CR also allowed us to discover that substitution at trifluoroethanol) did not improve the results. However, a
the N-6 position is indeed well tolerated as far as anti- net increase in reactivity was observed when a more elec-
5164
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5162–5175

Isocyanide-Based Multicomponent Reactions
tron-rich amine was used, the reaction with p-methoxyben-
zylamine affording the expected product 7b in 58% yield
(Entry 2).
Table 2. Intramolecular Ugi 4-CRs starting from oxo acid 6.
Scheme 6. Deprotection of indolobenzazepinones 7.
Removal of the PMB group of 26 was then attempted in
order to provide derivatives suitable for biological studies.
Despite many experiments, this group appeared resistant to
cleavage either under oxidizing conditions (CAN, DDQ) or
by catalytic hydrogenation. In order to circumvent this
problem, we attempted to avoid the use of a protecting
group altogether, by using ammonia in the Ugi 4-CR. We
were thus very pleased to observe that the use of a solution
of ammonia in ethanol (2 ) afforded the expected product
7i in 38% yield, a result that was further improved by con-
centrating the reaction medium to 0.5 . Under these con-
ditions, treatment with tert-butyl, benzyl, and n-butyl isocy-
anides led to indolobenzazepinones 7i, 7j, and 7k, respec-
tively, in 44%, 49%, and 47% yields (Entries 9–11). Re-
moval of the N,N-dimethylsulfamoyl groups from 7i and 7j
by the acidic treatment described above finally afforded the
expected deprotected paullone analogues 27 and 28 in 71%
and 93% yields, respectively.
Entry R1NH2
R2NC
R4
Product Yield[a]
1
2
3
4
5
6
7
8
tBu: 13g
tBu: 14g
H: 6a
7a
7b
7c
7d
7e
7f
8
58
traces
60
traces
77
83
89
44
49
PMB: 13b tBu: 14g
H: 6a
tBu: 13g
PMB: 13b tBu: 14g
tBu: 13g tBu: 14g
PMB: 13b tBu: 14g
allyl: 13e tBu: 14g
DMB: 13h tBu: 14g
H
H
H
tBu: 14g
Bn: 6b
Bn: 6b
SO2NMe2: 6c
SO2NMe2: 6c
SO2NMe2: 6c
SO2NMe2: 6c
SO2NMe2: 6c
SO2NMe2: 6c
7g
7h
7i
9
10
11
tBu: 14g
Bn: 14e
n-C4H9: 14b SO2NMe2: 6c
7j
7k
47
[a] Isolated yields after flash chromatography on silica gel.
We then studied the case of protected indolic substrates
that were accessible by simple protection of compound 23.
This was treated with benzyl bromide or N,N-dimethylsul-
famoyl chloride to afford the N-protected derivatives 24 and
25, respectively, in 85 and 73% yields. Saponification with
aqueous LiOH led to acids 6b and 6c, again in quantitative
yields.[20] These were then engaged in intramolecular Ugi 4-
CRs. As in the case of unprotected indole 6a, treatment of
6b and 6c with tert-butylamine (13g) and tert-butyl isocya-
nide (14g) did not give satisfactory results (Entries 3 and 5),
with only traces of the expected products being obtained.[21]
However, indole 6b proved to be as reactive with p-meth-
oxybenzylamine (13b) as the unprotected oxo acid 6a had
been, the indolobenzazepinone 7d being isolated with a sim-
ilar yield of 60% (Entry 4). More interestingly, though, we
found that use of the N,N-dimethylsulfamoyl analogue 6c
significantly improved results, with product 7f being ob-
tained in a better yield of 77% (Entry 6). Yields were fur-
ther improved by the use of allylamine (13e) and 2,4-di-
methoxybenzylamine (13h), with the corresponding indolo-
benzazepinones 7g and 7h being formed in 83% and 89%
yields, respectively (Entries 7 and 8).
Conclusions
In conclusion, we have demonstrated that application of
an intramolecular isocyanide-based multicomponent reac-
tion gives access to indolobenzazepinones in good yields of
up to 89%. Large molecular diversity can be generated in
a single step, as well as by further modifications of cyclo-
hexenamide derivatives such as 5m. In particular, the wide
variety of commercially available isocyanides should allow
efficient screening of the substitution pattern at C5 crucial
for the antimitotic activity of these indolobenzazepin-
ones.[11] Moreover, the use of tert-butylamine or ammonia
as the amine partner in the Ugi 4-CR has proven to be
optimal for the subsequent isolation of the deprotected tar-
get products necessary for biological testing. However, this
study also allowed us to find that introduction of substitu-
ents at the N-6 position has no detrimental effect on the
antimitotic activity. These compounds are currently under
investigation, and results will be reported in due course.
Deprotection of the Ugi 4-CR products 7 was then inves-
tigated. We first concentrated on the removal of the dimeth-
ylsulfamoyl group, since we had previously demonstrated
that this can be cleaved under acidic conditions by use of Experimental Section
a 1:1:10 mixture of anisole/trifluoromethanesulfonic acid/
General Remarks: Melting points, measured in capillary tubes and
trifluoroacetic acid.[22] Application of these conditions to
indolobenzazepinone 7d thus afforded the free NH-indole
derivative 26 in 86% yield (Scheme 6), while the PMB
group and tert-butyl amide surprisingly proved to be resist-
ant.
recorded with a Büchi B-540 melting point apparatus, are uncor-
rected. Infrared spectra were recorded on a Perkin–Elmer Spec-
trum BX FT-IR spectrometer. Optical rotations were determined
with a JASCO P-1010 polarimeter. Proton (1H) and carbon (13C)
NMR spectra were recorded on Bruker spectrometers: Avance 300
Eur. J. Org. Chem. 2008, 5162–5175
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5165

S. Beaumont, P. Retailleau, P. Dauban, R. H. Dodd
FULL PAPER
NMR or 500 NMR (300 and 500 MHz, respectively). Chemical (dd, J = 9.0, 2.4 Hz, 1 H, ArH), 6.88 (d, J = 2.4 Hz, 1 H, ArH),
shifts (δ) are reported in parts per million (ppm) with reference to 5.07 (s, 2 H, CH2Ph), 4.51 (q, J = 7.2 Hz, 2 H, CH3–CH2), 1.45 (t,
tetramethylsilane (TMS) as internal standard. NMR experiments J = 7.2 Hz, 3 H, CH3–CH2) ppm. 13C NMR (CDCl3, 75.5 MHz,
were carried out in deuteriochloroform (CDCl3) or in deuterioben-
zene (C6D6). The following abbreviations are used for the proton
spectra multiplicities: s: singlet, d: doublet, t: triplet, q: quartet, m:
multiplet. Coupling constants (J) are reported in Hertz [Hz]. Mass
spectra were obtained with an LCT (Micromass) instrument by
electrospray ionization and with a Time of Flight (TOF) analyzer
(ESI-MS) for high-resolution mass spectra (HRMS). Thin-layer
chromatography was performed on silica gel 60 plates with a fluo-
rescent indicator, with visualization under a UVP Mineralight
UVGL-58 lamp (254 nm) and by use of a 7% solution of phos-
phomolybdic acid in ethanol. Flash chromatography was per-
formed on silica gel 60 (40–63 µm, 230–400 mesh ASTM) at me-
dium pressure (200 mbar). All solvents were distilled and stored
over molecular sieves (4 Å) before use. All reagents were obtained
from commercial suppliers unless otherwise stated. Organic ex-
tracts were, in general, dried with magnesium sulfate (MgSO4) or
sodium sulfate (Na2SO4). Elemental analyses were performed at
the ICSN, CNRS, Gif-sur-Yvette, France.
25 °C): δ = 161.7 (CO), 156.7 (CO), 137.1 (C), 136.5 (C), 134.1
(ArCH), 132.7 (C), 130.2 (C), 129.1 (2ϫArCH), 128.6 (2ϫArCH),
128.2 (ArCH), 127.7 (2ϫArCH), 127.4 (C), 127.3 (2ϫArCH),
117.6 (ArCH), 116.1 (ArCH), 106.2 (ArCH), 74.0 (CI), 70.6
(CH Ph), 62.8 (CH –CH ), 14.1 (CH –CH ) ppm. FTIR: ν = 1727,
˜
2
3
2
3
2
1152 cm–1. HRMS (ESI+) calcd. for [C24H20INNaO4S]+: 584.0005;
found 584.0026.
General Procedure for Suzuki Cross-Coupling Reactions. Syntheses
of Compounds 12a–12c: CsF (151.8 mg, 1.0 mmol, 4 equiv.) was
fused under vacuum in a two-necked, round-bottomed flask. After
the system had cooled to room temperature, 2-formylphenylbo-
ronic acid (75 mg, 0.5 mmol, 2 equiv.) and dry degassed dioxane
(2.5 mL) were added under argon. The ethyl 3-iodoindole-2-car-
boxylate 11 (0.25 mmol, 1 equiv.), palladium diacetate (1.68 mg,
0.007 mmol, 3 mol-%), dppf (6.23 mg, 0.011 mmol, 4.5 mol-%),
and dry degassed dioxane (5 mL) were placed in a second round-
bottomed flask under argon. This second reaction mixture was
stirred at room temperature for 30 min and was then added to the
2-formylbenzeneboronic acid by cannula. This mixture was stirred
under argon at 80 °C until complete conversion of the starting in-
dole. Ice-cooled water was then added, and the solution was ex-
tracted with CH2Cl2 (2ϫ20 mL). The combined organic extracts
were dried (MgSO4) and filtered, and the solvents were evaporated.
The residue was purified by flash chromatography on silica gel
(heptane/EtOAc, 95:5 to 75:25).
General Procedure for the Synthesis of Ethyl 3-Iodo-1-phenylsul-
fonyl-1H-indole-2-carboxylates 11a–11c: A solution of the corre-
sponding iodide (14.8 mmol, 1 equiv.) in THF (70 mL) was added
at 0 °C under argon to a suspension of sodium hydride (892 mg,
22.3 mmol, 60% in oil, 1.5 equiv.) in dry THF (70 mL). The reac-
tion mixture was stirred for 45 min, and benzenesulfonyl chloride
(6.0 mL, 29.8 mmol, 2 equiv.) was added. The reaction mixture was
allowed to warm to room temperature overnight. The solvent was
removed in vacuo, and the residue was partitioned between CH2Cl2
(100 mL) and water (20 mL). The aqueous layer was extracted with
CH2Cl2 (3ϫ20 mL). The combined organic extracts were washed
with water (40 mL) and an aqueous solution of NaHCO3 (1 ,
2ϫ20 mL), dried (MgSO4), filtered, and concentrated in vacuo.
The resulting brown oil was dissolved in hot hexane/Et2O (1:1) and
crystallized at 0 °C to give the ethyl 3-iodo-1-(phenylsulfonyl)-1H-
indole-2-carboxylates.
Ethyl 3-(2-Formylphenyl)-1-phenylsulfonyl-1H-indole-2-carboxylate
(12a): Yield 85.6 mg (79%). White foam. 1H NMR (CDCl3,
500 MHz, 25 °C): δ = 9.67 (s, 1 H, CHO), 8.12 (d, J = 7.6 Hz, 1
H, ArH), 8.04 (d, J = 7.6 Hz, 1 H, ArH), 8.01 (d, J = 7.6 Hz, 1 H,
ArH), 7.61 (t, J = 7.6 Hz, 1 H, ArH), 7.55 (t, J = 7.6 Hz, 1 H,
ArH), 7.53 (t, J = 7.6 Hz, 1 H, ArH), 7.47 (d, J = 7.6 Hz, ArH,
2H), 7.43 (t, J = 7.6 Hz, 1 H, ArH), 7.33 (d, J = 7.6 Hz, 1 H, ArH),
7.22 (t, J = 7.6 Hz, 1 H, ArH), 7.15 (d, J = 7.6 Hz, 1 H, ArH),
4.19 (q, J = 7.3 Hz, 2 H, CH3–CH2), 1.06 (t, J = 7.3 Hz, 3 H, CH3–
CH2) ppm. 13C NMR (CDCl3, 75.5 MHz, 25 °C): δ = 191.1 (CO),
161.5 (CO), 137.6 (C), 136.3 (C), 135.1 (C), 134.4 (ArCH), 133.8
(ArCH), 131.5 (ArCH), 130.5 (C), 129.9 (C), 129.3 (ArCH), 129.2
(2ϫArCH), 127.7 (ArCH), 127.6 (ArCH), 127.5 (2ϫArCH), 125.0
(ArCH), 124.3 (C), 121.2 (ArCH), 115.5 (ArCH), 62.5 (CH3–CH2),
Ethyl 3-Iodo-1-phenylsulfonyl-1H-indole-2-carboxylate (11a):[11]
Yield 5.7 g (85%). White solid; m.p. 139 °C (hexane/Et2O). 1H
NMR (250 MHz, CDCl3, 25 °C): δ = 8.00 (d, J = 7.5 Hz, 3 H,
ArH), 7.60–7.30 (m, 6 H, ArH), 4.54 (q, J = 7.1 Hz, 2 H, CH3–
CH2), 1.48 (t, J = 7.1 Hz, 3 H, CH3–CH2) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 161.7 (CO), 137.3 (C), 135.5 (C),
134.2 (ArCH), 133.4 (C), 131.4 (C), 129.1 (2ϫArCH), 127.4
(ArCH), 127.3 (2ϫArCH), 124.8 (ArCH), 123.1 (ArCH), 114.7
13.7 (CH CH ) ppm. FTIR: ν = 2751, 1728, 1697 cm–1. HRMS
˜
3
2
(ESI+) calcd. for [C24H19NNaO5S]+: 456.0848; found 456.0861.
Ethyl 5-Fluoro-3-(2-formylphenyl)-1-phenylsulfonyl-1H-indole-2-car-
boxylate (12b): Yield 93.7 mg (83%). White foam. 1H NMR
(CDCl3, 500 MHz, 25 °C): δ = 9.67 (s, 1 H, CHO), 8.09 (dd, J =
8.8, 4.1 Hz, 1 H, ArH), 8.05 (d, J = 7.5 Hz, 1 H, ArH), 7.99 (d, J
= 8.2 Hz, 2 H, ArH), 7.63 (t, J = 8.2 Hz, 1 H, ArH), 7.59 (t, J =
7.5 Hz, 1 H, ArH), 7.56 (t, J = 7.5 Hz, 1 H, ArH), 7.63 (t, J =
8.2 Hz, 2 H, ArH), 7.33 (d, J = 7.5 Hz, 1 H, ArH), 7.17 (td, J =
8.8, 2.4 Hz, 1 H, ArH), 7.17 (dd, J = 8.2, 2.4 Hz, 1 H, ArH), 4.21
(q, J = 7.3 Hz, 2 H, CH3–CH2), 1.09 (t, J = 7.3 Hz, 3 H, CH3–
CH2) ppm. 13C NMR (CDCl3, 75.5 MHz, 25 °C): δ = 190.8 (CO),
161.2 (CO), 160.5 (d, J = 243.6 Hz, CF), 137.3 (C), 135.0 (C), 134.6
(ArCH), 133.9 (ArCH), 133.7 (C), 132.5 (C), 131.6 (C), 131.4
(ArCH), 129.5 (ArCH), 129.3 (2ϫArCH), 128.0 (ArCH), 127.5
(2ϫArCH), 123.9 (d, J = 3.8 Hz, 1 C), 116.9 (d, J = 9.0 Hz,
ArCH), 115.8 (d, J = 25.5 Hz, ArCH), 106.7 (d, J = 24.6 Hz,
(ArCH), 73.5 (CI), 62.8 (CH CH ), 14.0 (CH CH ) ppm. FTIR: ν
˜
3
2
3
2
= 3065, 1729, 1192, 726 cm–1.
Ethyl
5-Fluoro-1-phenylsulfonyl-1H-3-iodoindole-2-carboxylate
(11b):[11] Yield 5.3 g (76%). White solid; m.p. 111 °C (hexane/
Et2O). 1H NMR (CDCl3, 300 MHz, 25 °C): δ = 7.92–7.96 (m, 3
H), 7.56 (tt, J = 7.4, 2.1 Hz, 1 H, ArH), 7.42–7.48 (m, 2 H, ArH),
7.13 (td, J = 8.8, 2.6 Hz, 1 H, ArH), 7.06 (dd, J = 8.8, 2.6 Hz, 1
H, ArH), 4.52 (q, J = 7.2 Hz, 2 H, CH3–CH2), 1.45 (t, J = 7.2 Hz,
3 H, CH3–CH2) ppm. 13C NMR (CDCl3, 75.5 MHz, 25 °C): δ =
161.7 (CO), 160.0 (d, J = 238.5 Hz, CF), 137.3 (C), 134.6 (C), 129.1
(2ϫArCH), 127.6 (2ϫArCH), 116.5 (d, J = 9.3 Hz, ArCH), 115.9
(d, J = 25.8 Hz, ArCH), 109.1 (d, J = 24.7 Hz, ArCH), 72.4 (CI),
63.2 (CH CH ), 14.3 (CH CH ) ppm. FTIR: ν = 1727, 1152 cm–1.
˜
3
2
3
2
Ethyl 5-Benzyloxy-3-iodo-1-phenylsulfonyl-1H-indole-2-carboxylate
(11c): Yield 7.8 g (94%). White solid; m.p. 149 °C (hexane/Et2O).
1H NMR (CDCl3, 300 MHz, 25 °C): δ = 7.89–7.92 (m, 3 H, ArH),
7.53 (tt, J = 7.5, 2.1 Hz, 1 H, ArH), 7.29–7.45 (m, 7 H, ArH), 7.08
ArCH), 62.7 (CH –CH ), 13.7 (CH CH ) ppm. FTIR: ν = 1726,
˜
3
2
3
2
1696, 1372, 1188, 1175 cm–1. HRMS (ESI+) calcd. for
[C24H18FNNaO5S]+: 474.0788; found 474.0781.
5166
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5162–5175

Isocyanide-Based Multicomponent Reactions
Ethyl 5-Benzyloxy-3-(2-formylphenyl)-1-phenylsulfonyl-1H-indole-2-
carboxylate (12c): Yield 126.8 mg (92%). Beige foam. 1H NMR
(CDCl3, 500 MHz, 25 °C): δ = 9.63 (s, 1 H, CHO), 8.06 (d, J =
7.6 Hz, 1 H, ArH), 8.04 (d, J = 9.1 Hz, 1 H, ArH), 7.97 (d, J =
8.0 Hz, 2 H, ArH), 7.63 (t, J = 7.6 Hz, 1 H, ArH), 7.58 (t, J =
7.6 Hz, 1 H, ArH), 7.56 (t, J = 7.5 Hz, 1 H, ArH), 7.47 (d, J =
8.0 Hz, 2 H, ArH), 7.26–7.34 (m, 5 H, ArH), 7.13 (dd, J = 9.1,
2.2 Hz, 1 H, ArH), 6.63 (d, J = 2.2 Hz, 1 H, ArH), 4.90 (s, 2 H,
CH2Ph), 4.21 (q, J = 7.3 Hz, 2 H, CH3–CH2), 1.10 (t, J = 7.3 Hz,
3 H, CH3–CH2) ppm. 13C NMR (CDCl3, 75.5 MHz, 25 °C): δ =
191.2 (CO), 161.5 (CO), 156.9 (CO), 137.4 (C), 136.6 (C), 135.1
(C), 134.5 (C), 134.4 (ArCH), 133.9 (ArCH), 131.6 (C), 131.4
(ArCH), 131.2 (C), 130.7 (C), 129.4 (ArCH), 129.3 (2ϫArCH),
128.8 (2ϫArCH), 128.3 (ArCH), 127.8 (2ϫArCH), 127.7 (ArCH),
127.5 (2ϫArCH), 124.7 (C), 117.5 (ArCH), 116.8 (ArCH), 104.3
(ArCH), 70.7 (CH2Ph), 62.6 (CH3–CH2), 13.8 (CH3CH2) ppm.
HRMS (ESI+) calcd. for [C23H17NNaO4]+: 394.1056; found
394.1047.
General Procedure for Ugi 4-CRs. Syntheses of Compounds 5a–5s:
The oxo acid 4 (0.134 mmol, 1 equiv.) and the corresponding pri-
mary amine 13 (0.134 mmol, 1 equiv.) were dissolved in methanol
(0.85 mL), and the solution was stirred at room temperature for
10 min. Isocyanide (0.134 mmol, 1 equiv.) was then added, and the
resulting mixture was heated at 50 °C overnight. Aqueous HCl
solution (0.1 , 1 mL) was added, and the mixture was stirred for
15 min at room temperature. Water (10 mL) was added, the mixture
was extracted with CH2Cl2 (3ϫ10 mL), the combined organic ex-
tracts were dried (MgSO4) and filtered, and the solvents were evap-
orated. The resulting brown oil was purified by flash chromatog-
raphy on silica gel (CH2Cl2/MeOH, 95:5) to give compounds 5a–
5s.
FTIR: ν = 1724, 1695, 1371, 1176 cm–1. HRMS (ESI+) calcd. for
6-Benzyl-N-cyclohexyl-7-oxo-5,6,7,8-tetrahydroindolo[2,3-d][2]benz-
azepine-5-carboxamide (5a): Yield 31.7 mg (51 %). White solid;
˜
[C31H25NNaO6S]+: 562.1301; found 562.1283.
1
m.p. 212 °C (Et2O). H NMR (CDCl3, 500 MHz, 25 °C): δ = 9.93
General Procedure for Saponification and Deprotection of Indoles
4a–4c: Aqueous LiOH (1 , 7.0 mmol, 7 mL, 5 equiv.) was added
to a solution of oxo ester 12 (1.40 mmol) in THF (9.5 mL), and
the solution was stirred at 60 °C overnight. The mixture was cooled
to 0 °C, aqueous HCl (1 ) was added until pH = 2–3, and the
resulting mixture was extracted with EtOAc (3ϫ20 mL). The com-
bined organic extracts were dried (MgSO4) and filtered, and the
solvents were evaporated. The resulting solid was directly used
without further purification.
(br. s, 1 H, NH), 8.03 (d, J = 7.7 Hz, 1 H, ArH), 7.95 (d, J =
8.1 Hz, 1 H, ArH), 7.50 (t, J = 7.7 Hz, 1 H, ArH), 7.46 (d, J =
8.1 Hz, 1 H, ArH), 7.27–7.34 (m, 6 H, ArH), 7.21 (t, J = 7.7 Hz,
1 H, ArH), 7.18 (t, J = 7.7 Hz, 1 H, ArH), 6.85 (t, J = 7.7 Hz, 1
H, ArH), 5.46 (d, J = 14.9 Hz, 1 H, CHPh AB system), 4.83–4.87
(m, 2 H, CH, NH), 4.69 (d, J = 14.9 Hz, 1 H, CHPh AB system),
3.21–3.29 (m, 1 H, CHCy), 1.23–1.42 (m, 4 H, CH2Cy), 0.98–1.07
(m, 2 H, CH2Cy), 0.76–0.87 (m, 2 H, CH2Cy), 0.62–0.70 (m, 2 H,
CH2Cy) ppm. 13C NMR (CDCl3, 75.5 MHz, 25 °C): δ = 168.0
(CO), 163.4 (CO), 136.8 (C), 136.5 (C), 134.6 (C), 132.9 (C), 130.6
(ArCH), 130.0 (C), 129.6 (ArCH), 129.3 (ArCH), 128.8 (ArCH),
128.5 (ArCH), 128.0 (ArCH), 127.1 (ArCH), 125.2 (ArCH), 125.0
3-(2-Formylphenyl)-1H-indole-2-carboxylic Acid (4a): Yield
356.5 mg (96%). White foam. 1H NMR (MeOD, 500 MHz, 25 °C):
δ = 9.80 (s, 1 H, CHO), 8.00 (d, J = 7.9 Hz, 1 H, ArH), 7.66 (t, J
= 7.3 Hz, 1 H, ArH), 7.47–7.53 (m, 3 H, ArH), 7.29–7.32 (m, 2 H, (C), 121.2 (ArCH), 121.1 (ArCH), 116.5 (C), 112.7 (ArCH), 66.2
ArH), 7.07 (t, J = 7.3 Hz, 1 H, ArH) ppm. 13C NMR (MeOD, (CH), 52.7 (CH2Ph), 48.2 (CHCy), 32.4 (CH2), 32.1 (CH2), 25.3
75.5 MHz, 25 °C): δ = 193.4 (CO), 163.5 (CO), 138.4 (C), 136.2
(CH ), 24.6 (CH ), 24.3 (CH ) ppm. FTIR: ν = 3306, 2929, 2437,
˜
2 2 2
(C), 134.9 (C), 133.7 (ArCH), 132.5 (ArCH), 128.9 (C), 127.9 1660, 1517 cm–1. HRMS (ESI+) calcd. for [C30H29N3NaO2]+:
(ArCH), 126.9 (ArCH), 126.1 (ArCH), 125.6 (C), 121.4 (ArCH), 486.2116; found 486.2157.
121.2 (ArCH), 118.7 (C), 112.5 (ArCH) ppm. FTIR: ν = 3180,
˜
N-Butyl-6-(4-methoxybenzyl)-7-oxo-5,6,7,8-tetrahydroindolo[2,3-d]-
[2]benzazepine-5-carboxamide (5b): Yield 35.1 mg (56%). White so-
lid; m.p. 184 °C (Et2O). H NMR (CDCl3, 500 MHz, 25 °C): δ =
2950, 1681, 1659, 1543, 745 cm–1. HRMS (ESI+) calcd. for
[C16H11NNaO3]+: 288.0637; found 288.0641.
1
5-Fluoro-3-(2-formylphenyl)-1H-indole-2-carboxylic Acid (4b): Yield
378.8 mg (93%). White foam. 1H NMR (MeOD, 500 MHz, 25 °C):
δ = 9.83 (s, 1 H, CHO), 8.02 (dd, J = 7.9, 1.3 Hz, 1 H, ArH), 7.72
(td, J = 7.6, 1.3 Hz, 1 H, ArH), 7.49–7.57 (m, 3 H, ArH), 7.13 (td,
J = 9.5, 2.4 Hz, 1 H, ArH), 6.96 (dd, J = 9.5, 2.4 Hz, 1 H,
9.15 (br. s, 1 H, NH), 7.93 (d, J = 7.7 Hz, 1 H, ArH), 7.88 (d, J =
8.1 Hz, 1 H, ArH), 7.41 (t, J = 7.7 Hz, 1 H, ArH), 7.37 (d, J =
8.1 Hz, 1 H, ArH), 7.24 (d, J = 7.7 Hz, 1 H, ArH), 7.10–7.16 (m,
4 H, ArH), 6.74 (d, J = 8.1 Hz, 1 H, ArH), 5.27 (d, J = 14.8 Hz,
1 H, CH2Ph AB system), 4.90 (br. s, 1 H, NH), 4.75 (s, 1 H, CH),
ArH) ppm. 13C NMR (MeOD, 75.5 MHz, 25 °C): δ = 193.0 (CO), 4.47 (d, J = 14.8 Hz, 1 H, CH2Ph AB system), 3.71 (s, 3 H, OCH3),
163.8 (CO), 154.5 (d, J = 238.8 Hz, CF), 135.2 (C), 134.3 (ArCH), 2.83–2.92 (m, 1 H, CH2N), 2.37–2.44 (m, 1 H, CH2N), 0.46–0.54
133.6 (C), 132.4 (C), 131.7 (C), 131.4 (ArCH), 129.7 (ArCH), 129.6
(C), 128.7 (C), 128.2 (ArCH), 117.3 (d, J = 9.4 Hz, ArCH), 114.9
(d, J = 26.3 Hz, ArCH), 106.8 (d, J = 24.8 Hz, ArCH) ppm. FTIR:
(m, 4 H, 2ϫCH2), 0.25 (t, J = 6.8 Hz, 3 H, CH3) ppm. 13C NMR
(CDCl3, 75.5 MHz, 25 °C): δ = 167.0 (CO), 163.2 (CO), 159.5
(CO), 136.4 (C), 134.6 (C), 133.0 (C), 130.8 (C), 130.7 (ArCH),
130.4 (C), 129.7 (ArCH), 128.8 (C), 128.5 (ArCH), 127.2 (ArCH),
125.4 (ArCH), 125.2 (C), 121.5 (ArCH), 121.4 (ArCH), 116.2 (C),
114.2 (ArCH), 112.6 (ArCH), 65.8 (CH), 55.5 (OCH3), 52.0
(CH2Ph), 39.6 (CH2), 31.5 (CH2), 19.6 (CH2), 13.5 (CH3) ppm.
ν = 3182, 2945, 1678, 1650, 1548, 746 cm–1. HRMS (ESI+) calcd.
˜
for [C16H10FNNaO3]+: 306.0543; found 306.0554.
5-Benzyloxy-3-(2-formylphenyl)-1H-indole-2-carboxylic Acid (4c):
1
Yield 452.4 mg (87%). White foam. H NMR (MeOD, 500 MHz,
FTIR: ν = 3267, 1655, 1609, 1510 cm–1. HRMS (ESI+) calcd. for
˜
25 °C): δ = 9.82 (s, 1 H, CHO), 8.00 (dd, J = 7.6, 1.1 Hz, 1 H,
ArH), 7.66 (td, J = 7.6, 1.1 Hz, 1 H, ArH), 7.52 (t, J = 7.6 Hz, 1
H, ArH), 7.44–7.45 (m, 2 H, ArH), 7.25–7.38 (m, 4 H, ArH), 7.08
(dd, J = 8.9, 2.1 Hz, 1 H, ArH), 6.80, (d, J = 2.1 Hz, 1 H, ArH),
[C29H29N3O3Na]+: 490.2114; found 490.2107. C29H29N3O3
(467.56): calcd. C 74.50, H 6.25, N 8.99; found C 74.19, H 6.55, N
8.94.
4.96 (s, 2 H, CH2Ph) ppm. 13C NMR (MeOD, 75.5 MHz, 25 °C): 6-Methyl-N-(2-morpholinoethyl)-7-oxo-5,6,7,8-tetrahydroindolo[2,3-
δ = 194.0 (CO), 164.6 (CO), 155.6 (C), 140.0 (C), 138.9 (C), 136.3 d][2]benzazepine-5-carboxamide (5c): Yield 18.5 mg (33%). White
1
(C), 137.4 (ArCH), 133.5 (ArCH), 133.2 (C), 130.1 (C), 129.5 solid; m.p. 237 °C (Et2O). H NMR (CDCl3, 500 MHz, 25 °C): δ
(2ϫArCH), 128.9 (ArCH), 128.8 (2ϫArCH, ArCH), 127.7
(ArCH), 119.0 (ArCH), 118.8 (C), 114.6 (ArCH), 103.4 (ArCH), = 8.1 Hz, 1 H, ArH), 7.58 (t, J = 7.7 Hz, 1 H, ArH), 7.46–7.48 (m,
71.7 (CH Ph) ppm. FTIR: ν = 3192, 2954, 1687, 1665, 1547 cm–1.
2 H, ArH), 7.40 (t, J = 7.3 Hz, 1 H, ArH), 7.31 (t, J = 7.7 Hz, 1
= 9.80 (br. s, 1 H, NH), 8.06 (d, J = 7.7 Hz, 1 H, ArH), 7.91 (d, J
˜
2
Eur. J. Org. Chem. 2008, 5162–5175
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5167

S. Beaumont, P. Retailleau, P. Dauban, R. H. Dodd
FULL PAPER
H, ArH), 7.17 (t, J = 7.7 Hz, 1 H, ArH), 5.89 (br. s, 1 H, NH), 7.47 (m, 2 H, ArH), 7.39 (td, J = 7.6, 0.9 Hz, 1 H, ArH), 7.31 (t,
4.85 (s, 1 H, CH), 3.40 (s, 3 H, NCH3), 3.38 (br. s, 4 H, 2ϫCH2O), J = 7.6 Hz, 1 H, ArH), 7.17 (t, J = 7.6 Hz, 1 H, ArH), 5.88 (br. t,
2.69–2.83 (m, 2 H, CH2NH), 1.98–2.04 (m, 2 H, CH2N), 1.85–1.91 J = 4.8 Hz, 1 H, NH), 4.89 (s, 1 H, CH), 3.94–4.00 (m, 1 H,
(m, 2 H, CH2N), 1.75–1.79 (m, 1 H, CHN), 1.62 (s, 9 H, tBu), 1.49– NCHpent AB system), 3.55–3.60 (m, 1 H, NCHpent AB system),
1.53 (m, 1 H, CHN) ppm. 13C NMR (CDCl3, 75.5 MHz, 25 °C): δ 3.35–3.43 (br. s, 4 H, 2ϫCH2O), 2.76–2.87 (m, 2 H, CH2NH),
= 168.9 (CO), 163.1 (CO), 136.4 (C), 134.5 (C), 133.0 (C), 130.9 2.01–2.09 (m, 2 H, CH2N), 1.92–1.97 (m, 2 H, CH2N), 1.84–1.89
(ArCH), 130.7 (C), 129.9 (ArCH), 128.6 (ArCH), 127.3 (ArCH), (m, 1 H, CHCH2pent AB system), 1.73–1.82 (m, 1 H, CHN), 1.60–
125.2 (ArCH), 124.9, (C), 121.3 (ArCH), 120.8 (ArCH), 112.9
(ArCH), 69.8 (CH), 67.0 (2 ϫ CH2O), 56.0 (CH2N), 52.9
1.66 (m, 2 H, CH2CH2pent), 1.21–1.35 (m, 4 H, CH2CH3pent, CHN,
CHCH2pent AB system), 0.84 (t, J = 8.2 Hz, 3 H, CH3) ppm. 13C
(2ϫCH N), 38.1 (CH ), 35.8 (CH NH) ppm. FTIR: ν = 3244, NMR (CDCl3, 75.5 MHz, 25 °C): δ = 168.8 (CO), 162.5 (CO),
˜
2
3
2
2826, 1672, 1613, 1504 cm– 1 . HRMS (ESI+ ) calcd. for
136.4 (C), 135.2 (C), 133.0 (C), 131.0 (C), 130.6 (ArCH), 129.8
[C24H26N4NaO3]+: 441.1903; found 441.1896. C24H26N4O3·0.6H2O (ArCH), 128.5 (ArCH), 127.2 (ArCH), 125.1 (ArCH), 124.9 (C),
(429.30): calcd. C 67.15, H 6.39, N 13.05; found C 66.84, H 6.59,
N 13.36.
121.2 (ArCH), 120.8 (ArCH), 115.6 (C), 112.8 (ArCH), 67.9 (CH),
67.0 (2ϫCH2O), 56.0 (CH2N), 52.9 (2ϫCH2N), 50.1 (CH2), 35.8
(CH2NH), 29.2 (CH2), 28.2 (CH2), 22.6 (CH2), 14.2 (CH3) ppm.
6-Isopropyl-N-(2-morpholinoethyl)-7-oxo-5,6,7,8-tetrahydroindolo-
[2,3-d][2]benzazepine-5-carboxamide (5d): Yield 28.7 mg (48%).
White solid; m.p. 262 °C (Et2O). 1H NMR (CDCl3, 500 MHz,
25 °C): δ = 9.78 (br. s, 1 H, NH), 8.04 (d, J = 7.7 Hz, 1 H, ArH),
7.90 (d, J = 8.1 Hz, 1 H, ArH), 7.54 (t, J = 7.7 Hz, 1 H, ArH),
FTIR: ν = 3333, 2961, 1665, 1621, 1496, 1115 cm–1. HRMS (ESI+)
˜
calcd. for [C28H34N4NaO3]+: 475.2709; found 475.2695.
C28H34N4O3·0.2 H2O (478.20): calcd. C 70.33, H 7.25, N 11.72;
found C 70.16, H 7.38, N 11.34.
7.46 (d, J = 8.1 Hz, 2 H, ArH), 7.36 (t, J = 7.3 Hz, 1 H, ArH), N-Butyl-6-(tert-butyl)-7-oxo-5,6,7,8-tetrahydroindolo[2,3-d][2]benz-
7.31 (t, J = 7.3 Hz, 1 H, ArH), 7.16 (t, J = 7.7 Hz, 1 H, ArH), 5.92 azepine-5-carboxamide (5g): Yield 29.7 mg (55 %). White solid;
1
(br. s, 1 H, NH), 5.10 (sept, J = 6.7 Hz, 1 H, CH), 4.98 (s, 1 H,
CH), 3.38 (br. s, 4 H, 2ϫCH2O), 2.73–2.84 (m, 2 H, CH2NH),
m.p. 205 °C (Et2O). H NMR (CDCl3, 500 MHz, 25 °C): δ = 9.16
(br. s, 1 H, NH), 8.09 (d, J = 7.6 Hz, 1 H, ArH), 7.97 (d, J =
2.02–2.06 (m, 2 H, CH2N), 1.93–1.97 (m, 2 H, CH2N), 1.83–1.87 7.6 Hz, 1 H, ArH), 7.57 (t, J = 7.6 Hz, 1 H, ArH), 7.47 (d, J =
(m, 1 H, CHN), 1.61–1.66 (m, 1 H, CHN), 1.38 (d, J = 6.7 Hz, 3 7.6 Hz, 1 H, ArH), 7.42 (d, J = 7.6 Hz, 1 H, ArH), 7.38 (t, J =
H, CH3), 1.22 (d, J = 6.7 Hz, 3 H, CH3) ppm. 13C NMR (CDCl3,
75.5 MHz, 25 °C): δ = 169.2 (CO), 162.4 (CO), 136.4 (C), 136.0
7.6 Hz, 1 H, ArH), 7.30 (t, J = 7.6 Hz, 1 H, ArH), 7.18 (t, J =
7.6 Hz, 1 H, ArH), 5.32 (s, 1 H, CH), 5.03 (br. s, 1 H, NH), 2.97–
(C), 133.2 (C), 131.3 (C), 130.3 (ArCH), 129.5 (ArCH), 128.4 3.04 (m, 2 H, CH2), 2.40–2.47 (m, 2 H, CH2), 1.62 (s, 9 H, tBu),
(ArCH), 127.2 (ArCH), 125.0 (ArCH), 124.9, (C), 121.2 (ArCH),
120.8 (ArCH), 115.3 (C), 112.8 (ArCH), 67.0 (2ϫ CH2O), 60.1
(CH), 56.0 (CH2N), 52.9 (2ϫCH2N), 46.5 (CH), 35.9 (CH2NH),
0.52–0.59 (m, 2 H, CH2), 0.39–0.48 (m, 2 H, CH2), 0.30 (t, J =
7.3 Hz, 3 H, CH3) ppm. 13C NMR (CDCl3, 75.5 MHz, 25 °C): δ =
167.0 (CO), 163.5 (CO), 136.5 (C), 136.0 (C), 133.1 (C), 132.2 (C),
130.1 (ArCH), 129.6 (ArCH), 128.4 (ArCH), 127.2 (ArCH), 125.2
(C), 125.1 (ArCH), 121.3 (ArCH), 121.2 (ArCH), 115.1 (C), 112.4
(ArCH), 63.4 (CH), 59.7 (C), 39.8 (CH2), 31.4 (CH2), 29.2 (tBu),
21.7 (CH ), 20.1 (CH ) ppm. FTIR: ν = 3236, 2956, 1665, 1601,
˜
3
3
1524 cm–1. HRMS (ESI+) calcd. for [C26H30N4NaO3]+: 447.2396;
found 447.2379. C26H30N4O3·0.1H2O (448.34): calcd. C 69.65, H
6.79, N 12.50; found C 69.28, H 6.98, N 12.58.
19.7 (CH ), 13.4 (CH ) ppm. FTIR: ν = 3290, 2958, 2927, 1660,
˜
2
3
1609, 1529 cm–1. HRMS (ESI+) calcd. for [C25H29N3NaO2]+:
6-Allyl-N-(2-morpholin-4-ylethyl)-7-oxo-5,6,7,8-tetrahydroindolo-
[2,3-d][2]benzazepine-5-carboxamide (5e): Yield 23.8 mg (40%).
White solid; m.p. 262 °C (Et2O). 1H NMR (CDCl3, 500 MHz,
25 °C): δ = 10.0 (br. s, 1 H, NH), 8.04 (d, J = 7.7 Hz, 1 H, ArH),
426.2158; found 426.2157.
6-tert-Butyl-N-(2-morpholinoethyl)-7-oxo-5,6,7,8-tetrahydroindolo-
[2,3-d][2]benzazepine-5-carboxamide (5h): Yield 34.6 mg (56%).
7.90 (d, J = 8.1 Hz, 1 H, ArH), 7.56 (t, J = 7.7 Hz, 1 H, ArH), White solid; m.p. 235 °C (Et2O). 1H NMR (CDCl3, 500 MHz,
7.47 (d, J = 8.2 Hz, 1 H, ArH), 7.35–7.40 (m, 2 H, ArH), 7.31 (t, 25 °C): δ = 9.28 (br. s, 1 H, NH), 8.09 (d, J = 7.7 Hz, 1 H, ArH),
J = 7.7 Hz, 1 H, ArH), 7.17 (t, J = 7.7 Hz, 1 H, ArH), 5.87–5.95 7.92 (d, J = 8.1 Hz, 1 H, ArH), 7.57 (t, J = 7.5 Hz, 1 H, ArH),
(m, 2 H, NH and CH), 5.32 (dd, J = 17.1, 1.2 Hz, 1 H, CH), 5.27 7.43 (d, J = 8.1 Hz, 1 H, ArH), 7.39 (t, J = 7.5 Hz, 1 H, ArH),
(dd, J = 10.1, 1.2 Hz, 1 H, CH), 4.94 (s, 1 H, CH), 4.70 (dd, J =
15.3, 5.8 Hz, 1 H, CH), 4.22 (dd, J = 15.3, 7.1 Hz, 1 H, CH), 3.38
7.30 (t, J = 7.7 Hz, 1 H, ArH), 7.16 (t, J = 7.7 Hz, 1 H, ArH), 5.77
(br. s, 1 H, NH), 5.34 (s, 1 H, CH), 3.38 (br. s, 4 H, 2ϫCH2O),
(br. s, 4 H, 2ϫCH2O), 2.75–2.86 (m, 2 H, CH2NH), 2.02–2.05 (m, 2.69–2.83 (m, 2 H, CH2NH), 1.98–2.04 (m, 2 H, CH2N), 1.85–1.91
2 H, CH2N), 1.92–1.96 (m, 2 H, CH2N), 1.84–1.88 (m, 1 H, CHN),
(m, 2 H, CH2N), 1.75–1.79 (m, 1 H, CHN), 1.62 (s, 9 H, tBu), 1.49–
1.63–1.68 (m, 1 H, CHN) ppm. 13C NMR (CDCl3, 75.5 MHz,
1.53 (m, 1 H, CHN) ppm. 13C NMR (CDCl3, 75.5 MHz, 25 °C): δ
25 °C): δ = 168.8 (CO), 162.8 (CO), 136.6 (C), 134.8 (C), 133.9 = 170.0 (CO), 163.6 (CO), 136.8 (C), 136.0 (C), 133.1 (C), 132.5
(CH), 133.1 (C), 130.8 (ArCH), 130.6 (C), 129.7 (ArCH), 128.5 (C), 130.1 (ArCH), 129.5 (C), 128.2 (ArCH), 127.2 (ArCH), 125.1
(ArCH), 127.2 (ArCH), 125.2 (ArCH), 124.9, (C), 121.2 (ArCH),
(ArCH), 125.0 (C), 121.2 (ArCH), 121.0 (ArCH), 114.9 (ArCH),
120.8 (ArCH), 119.3 (CH2), 115.8 (C), 112.9 (ArCH), 67.0 112.6 (ArCH), 67.0 (2ϫCH2O), 63.3 (CH), 59.7 (C), 56.0 (CH2N),
(2ϫCH2O), 65.9 (CH), 56.0 (CH2N), 52.9 (2ϫCH2N), 51.8 (CH2),
52.9 (2ϫCH N), 35.9 (CH NH), 29.2 (tBu) ppm. FTIR: ν = 3274,
˜
2 2
35.8 (CH NH) ppm. FTIR: ν = 3257, 2956, 1652, 1611, 1531,
1666, 1610, 1530 cm–1. HRMS (ESI+) calcd. for [C27H32N4NaO3]+:
461.2569; found 461.2553.
˜
2
1115 cm–1. HRMS (ESI+) calcd. for [C26H28N4O3Na]+: 445.2240;
found 445.2236. C26H28N4O3 (444.53): calcd. C 70.25, H 6.35, N
12.60; found C 69.94, H 6.58, N 12.29.
Methyl N-[(6-tert-Butyl-7-oxo-5,6,7,8-tetrahydroindolo[2,3-d][2]benz-
azepin-5-yl)carbonyl]glycinate (5i): Yield 20.8 mg (37 %). White
amorphous solid. 1H NMR (CDCl3, 500 MHz, 25 °C): δ = 9.45
(br. s, 1 H, NH), 8.09 (d, J = 7.8 Hz, 1 H, ArH), 8.00 (d, J =
8.0 Hz, 1 H, ArH), 7.55 (td, J = 7.5, 1.3 Hz, 1 H, ArH), 7.43–7.47
N-(2-Morpholinoethyl)-7-oxo-6-pentyl-5,6,7,8-tetrahydroindolo[2,3-
d][2]benzazepine-5-carboxamide (5f): Yield 34.3 mg (54%). White
1
solid; m.p. 219 °C (Et2O). H NMR (CDCl3, 500 MHz, 25 °C): δ
= 9.62 (br. s, 1 H, NH), 8.04 (d, J = 7.6 Hz, 1 H, ArH), 7.90 (d, J (m, 2 H, ArH), 7.35 (td, J = 7.5, 1.3 Hz, 1 H, ArH), 7.30 (td, J =
= 7.6 Hz, 1 H, ArH), 7.57 (td, J = 7.6, 1.2 Hz, 1 H, ArH), 7.45– 8.1, 1.3 Hz, 1 H, ArH), 7.18 (td, J = 8.1, 1.3 Hz, 1 H, ArH), 5.64
5168
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5162–5175

Isocyanide-Based Multicomponent Reactions
(br. s, 1 H, NH), 5.40 (s, 1 H, CH), 3.62 (dd, J = 18.3, 5.5 Hz, 1
= 9.24 (br. s, 1 H, NH), 8.09 (d, J = 7.7 Hz, 1 H, ArH), 7.98 (d, J
H, CH), 3.37 (dd, J = 18.3, 5.5 Hz, 1 H, CH), 3.33 (s, 3 H, CH3), = 8.1 Hz, 1 H, ArH), 7.57 (t, J = 7.7 Hz, 1 H, ArH), 7.48 (d, J =
1.63 (s, 9 H, tBu) ppm. 13C NMR (CDCl3, 75.5 MHz, 25 °C): δ =
7.7 Hz, 1 H, ArH), 7.43 (d, J = 8.1 Hz, 1 H, ArH), 7.38 (t, J =
170.4 (CO), 169.9 (CO), 163.5 (CO), 136.2 (C), 135.8 (C), 133.2 7.7 Hz, 1 H, ArH), 7.31 (t, J = 7.7 Hz, 1 H, ArH), 7.19 (t, J =
(C), 132.1 (C), 130.1 (ArCH), 129.7 (ArCH), 128.4 (ArCH), 127.3 7.7 Hz, 1 H, ArH), 5.87 (s, 1 H, NH), 5.38 (s, 1 H, CH), 5.23 (br.
(ArCH), 125.1 (ArCH), 121.6 (ArCH), 121.1 (ArCH), 115.2 (C), t, 1 H, CH), 1.72–1.77 (m, 2 H, CH2), 1.62 (s, 9 H, tBu), 1.22–1.28
112.5 (ArCH), 63.3 (CH), 59.9 (C), 52.2 (OCH3), 41.7 (CH2), 29.2
(m, 6 H, 3ϫCH2) ppm. 13C NMR (CDCl3, 75.5 MHz, 25 °C): δ =
168.4 (CO), 163.5 (CO), 140.9 (C), 136.3 (C), 136.1 (C), 133.1 (C),
132.3 (C), 132.2 (C), 130.0 (ArCH), 129.7 (ArCH), 128.5 (ArCH),
127.3 (ArCH), 125.1 (ArCH), 121.2 (ArCH), 121.1 (ArCH), 116.8
(ArCH), 115.1 (C), 112.5 (CH), 63.6 (CH), 59.8 (C), 29.2 (tBu),
(tBu) ppm. FTIR: ν = 3273, 1732, 1680, 1614 cm–1. HRMS (ESI+)
˜
calcd. for [C24H25N3O4Na]+: 442.1743; found 442.1743.
N-Benzyl-6-tert-butyl-7-oxo-5,6,7,8-tetrahydroindolo[2,3-d][2]benz-
azepine-5-carboxamide (5j): Yield 33.4 mg (57%). White solid; m.p.
27.3 (CH ), 24.0 (CH ), 22.3 (CH ), 21.6 (CH ) ppm. FTIR: ν =
˜
2
2
2
2
1
240 °C (Et2O). H NMR (CDCl3, 500 MHz, 25 °C): δ = 9.20 (br.
3293, 2921, 1665, 1603, 1515, 1191 cm–1. HRMS (ESI+) calcd. for
[C27H29N3O2Na]+: 450.2158; found 450.2157. C27H29N3O2·0.4H2O
(434.74): calcd. C 74.59, H 6.91, N 9.67; found C 74.38, H 7.07, N
9.49.
s, 1 H, NH), 8.09 (d, J = 8.0 Hz, 1 H, ArH), 7.96 (d, J = 8.0 Hz,
1 H, ArH), 7.53 (t, J = 7.6 Hz, 1 H, ArH), 7.45–7.48 (m, 2 H,
ArH), 7.38 (t, J = 7.6 Hz, 1 H, ArH), 7.35 (t, J = 7.6 Hz, 1 H,
ArH), 7.23 (t, J = 7.6 Hz, 1 H, ArH), 6.91 (t, J = 7.1 Hz, 1 H,
ArH), 6.67 (t, J = 7.6 Hz, 2 H, ArH), 6.32 (d, J = 7.6 Hz, 2 H,
ArH) 5.42 (s, 1 H, CH), 5.38 (s, 1 H, NH), 4.45 (dd, J = 15.1 Hz,
1 H, CHBn AB system), 3.68 (dd, J = 15.1 Hz, 1 H, CHBn AB
system) 1.63 (s, 9 H, tBu) ppm. 13C NMR (CDCl3, 75.5 MHz,
25 °C): δ = 170.1 (CO), 163.5 (CO), 137.4 (C), 136.1 (C), 135.9 (C),
133.1 (C), 132.2 (C), 130.2 (ArCH), 129.7 (ArCH), 128.5 (ArCH),
128.4 (ArCH), 127.2 (ArCH), 127.1 (ArCH), 126.9 (ArCH), 125.4
(C), 125.3 (ArCH), 121.7 (ArCH), 121.5 (ArCH) 115.0 (C), 112.6
(ArCH), 63.5 (CH), 59.8 (C), 43.9 (CH2), 29.2 (tBu) ppm. FTIR:
6-tert-Butyl-11-fluoro-N-(2-morpholinoethyl)-7-oxo-5,6,7,8-tetrahy-
droindolo[2,3-d][2]benzazepine-5-carboxamide (5n): Yield 25.0 mg
(39 %). White solid; m.p. 279 °C (Et2O). 1H NMR (CDCl3,
500 MHz, 25 °C): δ = 9.35 (br. s, 1 H, NH), 7.99 (d, J = 7.6 Hz, 1
H, ArH), 7.58 (td, J = 7.6, 1.0 Hz, 1 H, ArH), 7.55 (dd, J = 9.8,
2.3 Hz, 1 H, ArH), 7.48 (d, J = 7.3 Hz, 1 H, ArH), 7.40 (t, J =
7.6 Hz, 1 H, ArH), 7.37 (dd, J = 8.8, 4.4 Hz, 1 H, ArH), 7.07 (td,
J = 8.8, 2.3 Hz, 1 H, ArH), 5.76 (br. s, 1 H, NH), 5.34 (s, 1 H,
CH), 3.39 (br. s, 4 H, 2ϫCH2O), 2.71–2.84 (m, 2 H, CH2NH),
2.01–2.06 (m, 2 H, CH2N), 1.88–1.92 (m, 2 H, CH2N), 1.78–1.83
(m, 1 H, CHN), 1.62 (s, 9 H, tBu), 1.54–1.59 (m, 1 H, CHN) ppm.
13C NMR (CDCl3, 75.5 MHz, 25 °C): δ = 169.8 (CO), 163.3 (CO),
158.5 (d, J = 236.0 Hz, CF), 136.7 (C), 134.0 (C), 132.8 (C), 132.5
(C), 130.2 (ArCH), 129.7 (ArCH), 127.8 (ArCH), 127.3 (ArCH),
125.2 (C), 125.1 (C), 114.9 (C), 113.6 (d, J = 26.4 Hz, ArCH), 113.4
(d, J = 9.2 Hz, ArCH), 105.5 (d, J = 24.1 Hz, ArCH), 67.0
(2ϫCH2O), 63.3 (CH), 59.8 (C), 56.1 (CH2N), 53.0 (2ϫCH2N),
ν = 3290, 1697, 1611, 1494, 1191 cm–1. HRMS (ESI+) calcd. for
˜
[C25H29N3NaO2]+: 460.2001; found 460.1967.
6-tert-Butyl-N-methyl-7-oxo-5,6,7,8-tetrahydroindolo[2,3-d][2]benz-
azepine-5-carboxamide (5k): Yield 19.9 mg (41 %). White solid;
1
m.p. 302 °C (Et2O). H NMR (CDCl3, 500 MHz, 25 °C): δ = 9.37
(br. s, 1 H, NH), 8.09 (d, J = 7.7 Hz, 1 H, ArH), 7.99 (d, J =
8.1 Hz, 1 H, ArH), 7.56 (t, J = 7.7 Hz, 1 H, ArH), 7.46 (d, J =
7.7 Hz, 1 H, ArH), 7.44 (d, J = 8.1 Hz, 1 H, ArH), 7.38 (t, J =
7.7 Hz, 1 H, ArH), 7.31 (t, J = 7.7 Hz, 1 H, ArH), 7.18 (t, J =
7.7 Hz, 1 H, ArH), 5.35 (s, 1 H, CH), 5.04 (d, J = 4.8 Hz, 1 H,
NH), 2.25 (d, J = 4.8 Hz, 3 H, CH3), 1.62 (s, 9 H, tBu) ppm. 13C
NMR (CDCl3, 75.5 MHz, 25 °C): δ = 170.6 (CO), 163.6 (CO),
136.3 (C), 136.1 (C), 133.2 (C), 132.2 (C), 130.1 (ArCH), 129.5
(ArCH), 128.4 (ArCH), 127.2 (ArCH), 125.0 (ArCH), 121.3
(ArCH), 121.1 (ArCH), 112.6 (ArCH), 63.3 (CH), 59.8 (C), 29.2
35.9 (CH NH), 29.2 (tBu) ppm. FTIR: ν = 3280, 1659, 1607,
˜
2
1535 cm–1. HRMS (ESI+) calcd. for [C27H31FN4NaO3]+: 479.2458;
found 479.2474.
Methyl N-[(6-tert-Butyl-11-fluoro-7-oxo-5,6,7,8-tetrahydroindolo-
[2,3-d][2]benzazepin-5-yl)carbonyl]glycinate (5o): Yield 22.3 mg
(38 %). White solid; m.p. 203 °C (Et2O). 1H NMR (CDCl3,
500 MHz, 25 °C): δ = 9.19 (br. s, 1 H, NH), 8.01 (d, J = 7.6 Hz, 1
H, ArH), 7.64 (dd, J = 9.8, 2.2 Hz, 1 H, ArH), 7.58 (td, J = 7.6,
0.9 Hz, 1 H, ArH), 7.40 (td, J = 7.6, 0.9 Hz, 1 H, ArH), 7.35 (dd,
J = 8.8, 4.4 Hz, 1 H, ArH), 7.07 (td, J = 8.8, 2.4 Hz, 1 H, ArH),
5.55 (br. s, 1 H, NH), 5.41 (s, 1 H, CH), 3.62 (dd, J = 18.3, 5.7 Hz,
1 H, CHNH), 3.39 (s, 3 H, OCH3), 3.38 (dd, J = 18.3, 5.7 Hz, 1
H, CHNH), 1.61 (s, 9 H, tBu) ppm. 13C NMR (CDCl3, 75.5 MHz,
25 °C): δ = 170.3 (CO), 169.8 (CO), 163.2 (CO), 158.8 (d, J =
236.5 Hz, CF), 135.7 (C), 133.6 (C), 132.8 (C), 132.6 (C), 130.2
(ArCH), 129.9 (ArCH), 128.0 (ArCH), 127.5 (ArCH), 125.4 (C),
125.3 (C), 115.1 (C), 115.0 (C), 113.9 (d, J = 26.7 Hz, ArCH), 113.3
(d, J = 9.1 Hz, ArCH), 106.4 (d, J = 24.3 Hz, ArCH), 63.2 (CH),
(tBu), 26.8 (CH ) ppm. FTIR: ν = 3260, 2961, 1668, 1635, 1615,
˜
3
1520 cm–1. HRMS (ESI+) calcd. for [C22H23N3O2Na]+: 384.1688;
found 384.1690. C22H23N3O2·0.3H2O (366.84): calcd. C 72.03, H
6.48, N 11.45; found C 71.66, H 6.58, N 11.17.
N,6-Di-tert-butyl-7-oxo-5,6,7,8-tetrahydroindolo[2,3-d][2]benzazep-
ine-5-carboxamide (5l): Yield 34.1 mg (63 %). White solid; m.p.
1
212 °C (Et2O). H NMR (CDCl3, 500 MHz, 25 °C): δ = 9.39 (br.
s, 1 H, NH), 8.06 (d, J = 7.7 Hz, 1 H, ArH), 7.97 (d, J = 8.0 Hz,
1 H, ArH), 7.55 (td, J = 7.5, 1.3 Hz, 1 H, ArH), 7.42–7.46 (m, 2
H, ArH), 7.37 (td, J = 7.5, 1.3 Hz, 1 H, ArH), 7.29 (td, J = 8.1,
1.3 Hz, 1 H, ArH), 7.19 (td, J = 8.1, 1.3 Hz, 1 H, ArH), 5.26 (s, 1
H, CH), 4.79 (s, 1 H, NH), 1.62 (s, 9 H, tBu), 0.59 (s, 9 H,
tBu) ppm. 13C NMR (CDCl3, 75.5 MHz, 25 °C): δ = 168.9 (CO),
163.6 (CO), 137.1 (C), 136.1 (C), 132.9 (C), 132.3 (C), 129.9
(ArCH), 129.5 (ArCH), 128.4 (ArCH), 127.2 (ArCH), 125.3 (C),
125.1 (ArCH), 121.3 (C), 120.9 (ArCH), 115.4 (C), 112.4 (C), 63.7
60.0 (C), 52.3 (OCH ), 41.6 (CH ), 29.2 (tBu) ppm. FTIR: ν =
˜
3
2
3274, 1752, 1693, 1600, 1194 cm–1. HRMS (ESI+) calcd. for
[C24H24FN3NaO4]+: 460.1649; found 460.1622.
N-Benzyl-6-tert-butyl-11-fluoro-7-oxo-5,6,7,8-tetrahydroindolo[2,3-
d][2]benzazepine-5-carboxamide (5p): Yield 31.7 mg (52%). White
(CH), 59.7 (C), 51.3 (C), 29.2 (tBu), 27.9 (tBu) ppm. FTIR: ν =
˜
1
solid; m.p. 272 °C (Et2O). H NMR (CDCl3, 500 MHz, 25 °C): δ
3263, 1679, 1614, 1498, 1194 cm–1. HRMS (ESI+) calcd. for
[C25H29N3NaO2]+: 426.2158; found 426.2157.
= 9.24 (br. s, 1 H, NH), 7.97 (d, J = 7.9 Hz, 1 H, ArH), 7.51–7.56
(m, 2 H, ArH), 7.46 (d, J = 7.3 Hz, 1 H, ArH), 7.35–7.41 (m, 2 H,
ArH), 7.13 (td, J = 8.8, 2.2 Hz, 1 H, ArH), 6.95 (t, J = 7.6 Hz, 1
H, ArH), 6.74 (t, J = 7.6 Hz, 2 H, ArH), 6.37 (d, J = 7.6 Hz, 2 H,
ArH), 5.41 (s, 1 H, CH), 5.35 (br. s, 1 H, NH), 4.36 (dd, J = 14.9,
6-tert-Butyl-N-(cyclohex-1-enyl)-7-oxo-5,6,7,8-tetrahydroindolo[2,3-
d][2]benzazepine-5-carboxamide (5m): Yield 18.3 mg (32%). White
1
solid; m.p. 260 °C (Et2O). H NMR (CDCl3, 500 MHz, 25 °C): δ
Eur. J. Org. Chem. 2008, 5162–5175
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5169

S. Beaumont, P. Retailleau, P. Dauban, R. H. Dodd
FULL PAPER
7.8 Hz, 1 H, CHPh AB system), 3.67 (dd, J = 14.9, 7.8 Hz, 1 H,
CHPh AB system), 1.63 (s, 9 H, tBu) ppm. 13C NMR (CDCl3,
75.5 MHz, 25 °C): δ = 169.7 (CO), 163.0 (CO), 159.7 (CF), 137.1
(C), 133.6 (C), 132.5 (C), 132.3 (C), 130.0 (ArCH), 129.6 (ArCH),
128.1 (2ϫArCH), 127.8 (ArCH), 127.2 (ArCH), 127.1 (ArCH),
126.8 (2ϫArCH), 125.3 (C), 125.2 (C), 114.8 (C), 114.7 (C), 114.0
(d, J = 26.9 Hz, ArCH), 113.5 (d, J = 9.6 Hz, ArCH), 106.4 (d, J
= 24.3 Hz, ArCH), 106.2 (C), 106.2 (C), 63.2 (CH), 59.7 (C), 43.7
59.6 (C), 51.3 (C), 29.2 (tBu), 28.0 (tBu) ppm. FTIR: ν = 3261,
˜
2964, 1692, 1612, 1500, 1193 cm–1. HRMS (ESI+) calcd. for
[C32H35N3NaO3]+: 532.2576; found 532.2572. C32H35N3O3
(509.64): calcd. C 75.41, H 6.92; found C 75.22, H 6.85.
6-tert-Butyl-7-oxo-5,6,7,8-tetrahydroindolo[2,3-d][2]benzazepine-5-
carboxamide (15): Acetyl chloride (42 µL, 0.585 mmol, 5 equiv.)
was added to a solution of indolobenzazepinone 5m (50 mg,
0.117 mmol, 1 equiv.) in distilled methanol (1.5 mL). The mixture
was stirred at room temperature for 30 min. The methanol was then
removed in vacuo, and the crude mixture was purified by flash
chromatography on silica gel (CH2Cl2/MeOH, 97:3) to give the title
compound (40.6 mg, 96%) as a white solid; m.p. 271 °C (CH2Cl2/
(CH ), 29.0 (tBu) ppm. FTIR: ν = 3269, 1674, 1612, 1501,
˜
2
1149 cm–1. HRMS (ESI+) calcd. for [C28H26FN3O2Na]+: 478.1907;
found 478.1889. C28H26FN3O2·0.04CHCl3 (460.30): calcd. C 73.17,
H 5.70, N 9.13; found C 72.88, H 5.64, N 9.03.
1
MeOH). H NMR (CDCl3, 500 MHz, 25 °C): δ = 9.68 (br. s, 1 H,
N,6-Di-tert-butyl-11-fluoro-7-oxo-5,6,7,8-tetrahydroindolo[2,3-d][2]-
benzazepine-5-carboxamide (5q): Yield 29.4 mg (52%). White solid;
NH), 8.08 (d, J = 7.7 Hz, 1 H, ArH), 7.99 (d, J = 7.7 Hz, 1 H,
ArH), 7.54 (t, J = 7.7 Hz, 1 H, ArH), 7.45 (d, J = 7.7 Hz, 1 H,
ArH), 7.41 (d, J = 7.7 Hz, 1 H, ArH), 7.36 (t, J = 7.7 Hz, 1 H,
ArH), 7.30 (t, J = 7.7 Hz, 1 H, ArH), 7.18 (t, J = 7.7 Hz, 1 H,
ArH), 5.35 (s, 1 H, CH), 5.20 (s, 1 H, NH), 5.04 (s, 1 H, NH), 1.59
(s, 9 H, tBu) ppm. 13C NMR (CDCl3, 75.5 MHz, 25 °C): δ = 172.
2 (CONH2), 163.7 (CO), 136.5 (C), 136.3 (C), 133.1 (C), 132.1 (C),
129.8 (ArCH), 129.5 (ArCH), 128.4 (ArCH), 127.2 (ArCH), 125.1
(ArCH), 121.4 (ArCH), 121.1 (ArCH), 115.7 (C), 112.9 (C), 112.7
1
m.p. 265 °C (Et2O). H NMR (CDCl3, 500 MHz, 25 °C): δ = 9.20
(br. s, 1 H, NH), 7.97 (d, J = 7.6 Hz, 1 H, ArH), 7.62 (dd, J = 8.8,
2.4 Hz, 1 H, ArH), 7.58 (td, J = 7.6, 1.2 Hz, 1 H, ArH), 7.46 (dd,
J = 7.6, 1.2 Hz, 1 H, ArH), 7.36–7.38 (m, 2 H, ArH), 7.07 (td, J
= 8.8, 2.4 Hz, 1 H, ArH), 5.25 (br. s, 1 H, CH), 4.76 (s, 1 H, NH),
1.61 (s, 9 H, tBu), 0.62 (s, 9 H, tBu) ppm. 13C NMR (CDCl3,
75.5 MHz, 25 °C): δ = 168.8 (CO), 163.3 (CO), 158.9 (d, J =
236.2 Hz, CF), 137.0 (C), 134.0 (C), 132.6 (C), 132.5 (C), 130.0
(ArCH), 129.6 (ArCH), 127.9 (ArCH), 127.4 (ArCH), 125.5 (C),
125.4 (C), 115.3 (C), 115.2 (C), 113.9 (d, J = 26.7 Hz, ArCH), 113.3
(d, J = 9.8 Hz, ArCH), 105.6 (d, J = 24.1 Hz, ArCH), 63.7 (CH),
(ArCH), 63.1 (CH), 59.8 (C), 29.2 (tBu) ppm. FTIR: ν = 3468,
˜
3245, 2977, 1695, 1614, 1410, 1194 cm–1. HRMS (ESI+) calcd. for
[ C 2 1 H 2 1 N 3 N a O 2 ]
+ : 3 7 0 . 1 5 3 1 ; f o u n d 3 7 0 . 1 5 2 9 .
C21H21N3O2·0.4CH3OH (475.58): calcd. C 71.35, H 6.32, N 11.66;
found C 71.41, H 6.61, N 11.29.
59.8 (C), 51.4 (C), 29.1 (tBu), 29.2 (tBu) ppm. FTIR: ν = 3246,
˜
1688, 1619, 1499 cm–1. HRMS (ESI+) calcd. for [C25H28FN3NaO2]+:
444.2064; found 444.2075.
6-tert-Butyl-7-oxo-5,6,7,8-tetrahydroindolo[2,3-d][2]benzazepine-5-
carbonitrile (16): DMSO (10.3 µL, 0.146 mmol, 2.4 equiv.) was
added at –78 °C to a suspension of indolobenzazepinone 15
(22 mg, 0.06 mmol, 1 equiv.) in distilled dichloromethane
(0.46 mL). Oxalyl chloride (7 µL, 0.08 mmol, 1.3 equiv.) was then
added, followed by triethylamine (40.5 µL, 0.304 mmol, 5 equiv.).
The mixture was allowed to warm to room temperature and stirred
for 1 h. Water (10 mL) was added, and the mixture was extracted
with ethyl acetate (2ϫ10 mL). The combined organic extracts were
dried (MgSO4), and the solvents were evaporated in vacuo. The
crude product was then purified by flash chromatography on silica
gel (CH2Cl2/MeOH, 97:3) to give the title compound (11 mg, 55%)
11-Benzyloxy-6-tert-butyl-N-(2-morpholinoethyl)-7-oxo-5,6,7,8-tetra-
hydroindolo[2,3-d][2]benzazepine-5-carboxamide (5r): Yield 42.5 mg
(56 %). White solid; m.p. 266 °C (Et2O). 1H NMR (CDCl3,
500 MHz, 25 °C): δ = 9.54 (br. s, 1 H, NH), 7.94 (d, J = 7.7 Hz, 1
H, ArH), 7.53 (td, J = 7.7, 1.4 Hz, 1 H, ArH), 7.26–7.53 (m, 9 H,
ArH), 7.06 (dd, J = 8.9, 2.4 Hz, 1 H, CHar), 5.81 (br. t, 1 H, NH),
5.32 (s, 1 H, CH), 5.10 (d, J = 14.0 Hz, 1 H, CHPh AB system),
5.06 (d, J = 14.0 Hz, 1 H, CHPh AB system), 3.39 (br. t, 4 H,
2 ϫ CH2O), 2.68–2.91 (m, 2 H, CH2NH), 2.02–2.09 (m, 2 H,
CH2N), 1.89–1.96 (m, 2 H, CH2N), 1.75–1.83 (m, 1 H, CHN), 1.61
(s, 9 H, tBu), 1.52–1.61 (m, 1 H, CHN) ppm. 13C NMR (CDCl3,
75.5 MHz, 25 °C): δ = 169.9 (CO), 163.5 (CO), 154.3 (CO), 137.1
(C), 136.6 (C), 133.2 (C), 133.1 (C), 131.6 (C), 130.1 (ArCH), 129.4
(ArCH), 128.8 (2ϫArCH), 128.2 (ArCH), 127.7 (2ϫArCH), 126.9
(ArCH), 125.3 (ArCH), 115.8 (ArCH), 114.7 (C), 113.4 (ArCH),
104.8 (ArCH), 71.3 (CH2Ph), 67.0 (2ϫCH2O), 63.3 (CH), 59.7 (C),
56.2 (CH2N), 53.0 (2ϫCH2N), 35.9 (CH2NH), 29.2 (tBu) ppm.
1
as a white solid; m.p. 228 °C (CH2Cl2/MeOH). H NMR (CDCl3,
500 MHz, 25 °C): δ = 9.32 (br. s, 1 H, NH), 8.14 (d, J = 7.7 Hz, 1
H, ArH), 8.08 (d, J = 8.1 Hz, 1 H, ArH), 7.57–7.62 (m, 1 H, ArH),
7.51 (d, J = 8.1 Hz, 1 H, ArH), 7.36–7.41 (m, 3 H, ArH), 7.26 (t,
J = 7.8 Hz, 1 H, ArH), 5.87 (s, 1 H, CH), 1.63 (s, 9 H, tBu) ppm.
13C NMR (CDCl3, 75.5 MHz, 25 °C): δ = 162.8 (CO), 136.6 (C),
133.1 (C), 132.7 (C), 130.4 (ArCH), 128.6 (ArCH), 128.3 (ArCH),
127.4 (ArCH), 126.9 (C), 126.0 (ArCH), 125.2 (C), 122.1 (ArCH),
121.8 (ArCH), 117.4 (C), 116.7 (C), 112.6 (ArCH), 60.9 (C), 48.9
FTIR: ν = 3261, 2964, 1692, 1612, 1500, 1193 cm–1. HRMS (ESI+)
˜
calcd. for [C34H38N4NaO4]+: 567.2971; found 567.2974.
C34H38N4O4·0.1CHCl3 (578.63): calcd. C 70.58, H 6.64, N 9.68;
found C 70.51, H 6.91, N 9.31.
(CH), 29.3 (tBu) ppm. FTIR: ν = 3278, 2922, 1730, 1627, 1523,
˜
1399, 1189 cm–1. HRMS (ESI+) calcd. for [C21H19N3ONa]+:
352.1426; found 352.1422.
11-Benzyloxy-N,6-di-tert-butyl-7-oxo-5,6,7,8-tetrahydroindolo[2,3-
d][2]benzazepine-5-carboxamide (5s): Yield 53.3 mg (78%). White
General Procedure for Deprotection of tert-Butyl Lactams 5g, 5h,
5q: Anisole (54 µL, 0.5 mmol, 10 equiv.) and TFA (0.57 mL,
7.5 mmol, 150 equiv.) were added to a solution of one of the tert-
butyl lactams 5g, 5h, or 5q (0.05 mmol, 1 equiv.) in CH2Cl2
(0.25 mL), and the reaction mixture was stirred at room tempera-
ture until complete conversion of starting material. Excess TFA
was then removed in vacuo, and the resulting solid was purified by
flash chromatography on silica gel (CH2Cl2/MeOH, 95:5).
1
solid; m.p. 241 °C (Et2O). H NMR (CDCl3, 500 MHz, 25 °C): δ
= 9.17 (br. s, 1 H, NH), 7.94 (d, J = 7.6 Hz, 1 H, ArH), 7.63 (t, J
= 7.6 Hz, 1 H, ArH), 7.28–7.47 (m, 9 H, ArH), 7.06 (dd, J = 8.9,
2.1 Hz, 1 H, ArH), 5.24 (br. s, 1 H, CH), 5.19 (d, J = 12.2 Hz, 1
H, CHPh AB system), 5.14 (d, J = 12.2 Hz, 1 H, CHPh AB sys-
tem), 4.79 (br. s, 1 H, NH), 1.61 (s, 9 H, tBu), 0.61 (s, 9 H,
tBu) ppm. 13C NMR (CDCl3, 75.5 MHz, 25 °C): δ = 169.0 (CO),
163.5 (CO), 154.3 (CO), 137.6 (C), 137.0 (C), 132.9 (C), 131.5 (C),
130.0 (ArCH), 129.4 (ArCH), 128.8 (2ϫArCH), 128.1 (ArCH),
127.9 (ArCH), 127.8 (2ϫArCH), 127.0 (ArCH), 116.3 (ArCH),
N-Butyl-7-oxo-5,6,7,8-tetrahydroindolo[2,3-d][2]benzazepine-5-car-
boxamide (17): Yield 13.9 mg (80%). Major rotamer. 1H NMR
115.1 (C), 113.2 (ArCH), 104.3 (ArCH), 71.3 (CH2), 63.7 (CH), (CD3CN, 500 MHz, 25 °C): δ = 11.20 (s, 1 H, NH), 8.00–8.10 (m,
5170
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5162–5175

Isocyanide-Based Multicomponent Reactions
2 H, ArH), 7.48–7.63 (m, 2 H, ArH), 7.33–7.42 (m, 2 H, ArH), 139.2 (C), 136.8 (C), 136.5 (C), 131.9 (ArCH), 131.5 (ArCH), 130.6
7.21–7.30 (m, 2 H, ArH), 4.91 (s, 1 H, CH), 2.81–2.91 (m, 1 H,
CHNH AB system), 2.61–2.68 (m, 1 H, CHNH AB system), 0.60–
0.75 (m, 4 H, 2ϫCH2), 0.33–0.46 (m, 3 H, CH3) ppm. 13C NMR
(CD3CN, 125 MHz, 25 °C): δ = 170.0 (CO), 162.7 (CO), 137.8
(ArCH), 137.6 (C), 134.5 (C), 133.7 (C), 131.8 (ArCH), 130.4 (C),
129.5 (ArCH), 128.2 (ArCH), 126.3 (C), 126.0 (ArCH), 122.4
(ArCH), 122.0 (ArCH), 117.6 (C), 113.5 (ArCH), 61.0 (CH), 39.7
(C), 130.2 (ArCH), 129.4 (C), 128.2 (ArCH), 124.4 (ArCH), 122.8
(ArCH), 120.5 (ArCH), 115.8 (ArCH), 109.4 (ArCH), 83.1
(ArCH), 52.3 (OCH ), 27.7 (tBu) ppm. FTIR: ν = 2979, 1722,
˜
3
1451, 1327, 1158, 745 cm– 1 . H RM S ( ES I+ ) calcd. for
[C21H21NNaO4]+: 374.1368; found 374.1353.
Methyl 2-(1H-Indol-2-yl)benzoate (22): TFA (4.3 mL, 56 mmol,
7 equiv.) was added to a solution of 21 (2.8 g, 8 mmol, 1 equiv.) in
CH2Cl2 (70 mL), and the solution was stirred at room temperature
for 12 h. Saturated aqueous NaHCO3 solution was added until
complete neutralization of TFA, and the mixture was extracted
with EtOAc (2ϫ50 mL). The combined organic extracts were dried
(MgSO4) and filtered, and the solvents were evaporated. The re-
(CH ), 32.2 (CH ), 20.2 (CH ), 1.8 (CH ) ppm. FTIR: ν = 3289,
˜
2
2
2
3
1660, 1606, 1194 cm–1. HRMS (ESI+) calcd. for [C21H21N3NaO]+:
370.1532; found 370.1528.
N-(2-Morpholinoethyl)-7-oxo-5,6,7,8-tetrahydroindolo[2,3-d][2]benz-
azepine-5-carboxamide (18): Yield 16.0 mg (79%). Major rotamer.
1H NMR (MeOD, 500 MHz, 25 °C): δ = 7.99–8.06 (m, 2 H, ArH), sulting solid was purified by flash chromatography on silica gel
7.51–7.61 (m, 3 H, ArH), 7.44 (t, J = 7.5 Hz, 1 H, ArH), 7.34 (t,
J = 7.5 Hz, 1 H, ArH), 7.21 (t, J = 7.5 Hz, 1 H, ArH), 5.02 (s, 1
H, CH), 3.42 (br. s, 4 H, 2ϫCH2O), 2.95–3.01 (m, 1 H, CHNH
(heptane/EtOAc, 1:1) to give 22 (1.86 g, 93%) as a white solid; m.p.
135 °C (heptane/EtOAc). H NMR (CDCl3, 500 MHz, 25 °C): δ =
9.59 (br. s, 1 H, NH), 7.78 (d, J = 7.7 Hz, 1 H, ArH), 7.74 (d, J =
1
AB system), 2.77–2.83 (m, 1 H, CHNH AB system), 1.93–2.04 (m, 7.7 Hz, 1 H, ArH), 7.62 (d, J = 7.7 Hz, 1 H, ArH), 7.54 (td, J =
4 H, 2ϫCH2N), 1.64–1.69 (m, 1 H, CHN AB system), 1.53–1.58 7.7, 1.5 Hz, 1 H, ArH), 7.42 (d, J = 7.7 Hz, 1 H, ArH), 7.38 (td, J
(m, 1 H, CHN AB system) ppm. 13C NMR (CDCl3, 75.5 MHz, = 7.7, 1.5 Hz, 1 H, ArH), 7.20 (td, J = 7.7, 1.5 Hz, 1 H, ArH),
25 °C): δ = 172.6 (CO), 166.6 (CO), 138.5 (C), 137.5 (C), 134.1 7.10, (td, J = 7.7, 1.5 Hz, 1 H, ArH), 6.70 (d, J = 1.5 Hz, 1 H,
(C), 131.9 (ArCH), 130.5 (ArCH), 129.9 (ArCH), 129.7 (C), 128.5
(ArCH), 126.4 (C), 126.2 (ArCH), 122.4 (2ϫArCH), 118.5 (C),
ArH), 3.83 (s, 3 H, OCH3) ppm. 13C NMR (CDCl3, 75.5 MHz,
25 °C): δ = 170.3 (CO), 137.1 (C), 136.8 (C), 133.0 (C), 131.9
113.9 (ArCH), 67.9 (2ϫ CH2O), 61.5 (CH), 57.9 (CH2N), 54.0 (ArCH), 131.1 (ArCH), 130.4 (ArCH), 130.2 (C), 128.6 (C), 127.7
(2 ϫ CH N), 36.9 (CH NH) ppm. FTIR: ν = 3278, 2922, 1730,
(ArCH), 122.6 (ArCH), 120.8 (ArCH), 120.2 (ArCH), 111.5
˜
2
2
1627, 1523, 1399, 1189 cm– 1 . HRMS (ESI+ ) calcd. for
(ArCH), 103.5 (ArCH), 53.0 (OCH ) ppm. FTIR: ν = 3360, 1719,
˜
3
[C21H19N3NaO]+: 352.1426; found 352.1422.
1258, 1088 cm–1. HRMS (ESI+) calcd. for [C16H13NNaO2]+:
274.0844; found 274.0837.
N-(tert-Butyl)-7-oxo-5,6,7,8-tetrahydroindolo[2,3-d][2]benzazepine-
5-carboxamide (19): Yield 17.3 mg (100 %). Major rotamer. 1H
Methyl 2-(3-Formyl-1H-indol-2-yl)benzoate (23): A mixture of
NMR (CD3CN, 500 MHz, 25 °C): δ = 11.32 (s, 1 H, NH), 9.40 (d, phosphoryl chloride (0.88 mL, 9.6 mmol, 1.5 equiv.) and N-methyl-
J = 5.1 Hz, 1 H, NH), 8.05 (d, J = 7.7 Hz, 1 H, ArH), 7.83 (d, J formanilide (1.18 mL, 9.6 mmol, 1.5 equiv.) was stirred at room
= 7.7 Hz, 1 H, ArH), 7.69 (d, J = 7.7 Hz, 1 H, ArH), 7.57 (t, J =
7.7 Hz, 1 H, ArH), 7.34 (t, J = 7.7 Hz, 1 H, ArH), 7.26 (t, J =
temperature for 15 min. A solution of 22 (1.6 g, 6.37 mmol,
1.0 equiv.) in 1,2-dichloroethane (32 mL) was added to the mixture,
7.7 Hz, 1 H, ArH), 7.18 (d, J = 7.7 Hz, 1 H, ArH), 7.03 (t, J = which was heated at reflux for 3 h. The warm mixture was poured
7.7 Hz, 1 H, ArH), 5.22 (d, J = 5.1 Hz, 1 H, CH), 0.94 (s, 9 H,
tBu) ppm. 13C NMR (CD3CN, 125 MHz, 25 °C): δ = 170.3 (CO),
165.5 (CO), 139.0 (C), 137.2 (C), 135.6 (C), 130.2 (C), 130.1
into a solution of sodium acetate in ice/water (5.1 g, 51 mL), stir-
ring was continued for 15 min, and the mixture was then extracted
with EtOAc (2ϫ25 mL). The combined organic extracts were dried
(ArCH), 129.8 (ArCH), 129.2 (ArCH), 129.0 (ArCH), 126.1 (C), (MgSO4) and filtered, and the solvents were evaporated. The re-
125.8 (ArCH), 123.4 (ArCH), 123.3 (ArCH), 122.9 (C), 114.2 sulting solid was purified by flash chromatography on silica gel
(ArCH), 59.0 (CH), 52.1 (C), 27.1 (tBu) ppm. FTIR: ν = 3289,
(heptane/EtOAc, 60:40) to give 23 (1.69 g, 95%) as a white solid;
m.p. 214 °C (heptane/EtOAc). 1H NMR (CDCl3 + MeOD,
500 MHz, 25 °C): δ = 9.57 (s, 1 H, CHO), 8.24 (dd, J = 6.0, 3.1 Hz,
1 H, ArH), 7.96 (d, J = 7.5 Hz, 1 H, ArH), 7.56 (t, J = 7.5 Hz, 1
H, ArH), 7.52 (t, J = 7.5 Hz, 1 H, ArH), 7.4 (d, J = 7.5 Hz, 1 H,
ArH), 7.34 (dd, J = 6.0, 3.1 Hz, 1 H, ArH), 7.20–7.23 (m, 2 H,
ArH), 3.66 (s, 3 H, OCH3) ppm. 13C NMR (CDCl3 + MeOD,
75.5 MHz, 25 °C): δ = 186.5 (CO), 167.5 (CO), 149.3 (C), 136.0
(C), 132.8 (ArCH), 131.8 (ArCH), 131.6 (C), 130.7 (ArCH), 130.5
(C), 129.9 (ArCH), 125.4 (C), 124.1 (ArCH), 123.0 (ArCH), 121.8
˜
1660, 1606, 1194 cm–1. HRMS (ESI+) calcd. for [C21H21N3ONa]+:
370.1532; found 370.1528. C21H21N3O2·0.5CH3OH (507.62): calcd.
C 71.05, H 6.38, N 11.56; found C 70.71, H 6.27, N 11.15.
Methyl 2-[1-(tert-Butoxycarbonyl)-1H-indol-2-yl]benzoate (21): De-
gassed aqueous Na2CO3 (2 , 17.3 mL, 34.6 mmol, 4.2 equiv.) was
added to a solution of 1-(tert-butoxycarbonyl)indole-2-boronic
acid (3 g, 11.5 mmol, 1.4 equiv.), methyl 2-iodobenzoate (2.15 g,
8.21 mmol, 1.0 equiv.), and tetrakis(triphenylphosphane)palladium
(474 mg, 0.41 mmol, 0.05 equiv.) in degassed DME (185 mL), and
the solution was stirred at reflux for 12 h. The mixture was cooled,
and water (150 mL) was added. The mixture was extracted with
EtOAc, the combined organic extracts were dried (MgSO4) and
filtered, and the solvents were evaporated. The resulting brown oil
was purified by flash chromatography on silica gel (heptane/EtOAc,
90:10) to give the cross-coupling product 21 (2.8 g, 97%) as a pale
yellow oil. 1H NMR (CDCl3, 500 MHz, 25 °C): δ = 8.27 (d, J =
7.7 Hz, 1 H, ArH), 8.04 (dd, J = 7.7, 1.2 Hz, 1 H, ArH), 7.54 (td,
J = 7.7, 1.2 Hz, 1 H, ArH), 7.52 (d, J = 7.7 Hz, 1 H, ArH), 7.45
(ArCH), 115.7 (C), 111.6 (ArCH), 52.6 (OCH ) ppm. FTIR: ν =
˜
3
3182, 1719, 1635, 1453, 1271, 743 cm–1. HRMS (ESI+) calcd. for
[C17H13NNaO3]+: 302.0793; found 302.0805.
Methyl 2-(1-Benzyl-3-formyl-1H-indol-2-yl)benzoate (24): A solu-
tion of 23 (0.15 g, 0.517 mmol, 1 equiv.) in dry THF (4 mL) was
added at 0 °C to a suspension of sodium hydride (31 mg,
0.78 mmol, 60% in oil, 1.5 equiv.) in dry THF (4 mL). The reaction
mixture was stirred for 45 min, and benzyl bromide (0.123 mL,
1.03 mmol, 2 equiv.) was added. The reaction mixture was allowed
(td, J = 7.7, 1.2 Hz, 1 H, ArH), 7.41 (d, J = 7.7 Hz, 1 H, ArH), to warm to room temperature and left stirring overnight. The sol-
7.31 (td, J = 7.7, 1.2 Hz, 1 H, ArH), 7.22, (t, J = 7.7 Hz, 1 H, ArH),
vent was removed in vacuo, and the residue was dissolved in
CH2Cl2 (15 mL) and water (15 mL). The aqueous layer was ex-
6.43 (s, 1 H, ArH), 3.65 (s, 3 H, OCH3), 1.24, (s, 9 H, tBu) ppm. 13
C
NMR (CDCl3, 75.5 MHz, 25 °C): δ = 167.1 (CO), 150.1 (CO), tracted with CH2Cl2 (3ϫ10 mL). The combined organic extracts
Eur. J. Org. Chem. 2008, 5162–5175
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5171

S. Beaumont, P. Retailleau, P. Dauban, R. H. Dodd
FULL PAPER
were dried (MgSO4) and filtered, and the solvents were evaporated.
The resulting brown oil was purified by flash chromatography on
silica gel (heptane/EtOAc, 1:1) to give 24 (0.162 g, 85%) as a yellow,
2-(1-Benzyl-3-formyl-1H-indol-2-yl)benzoic Acid (6b): Yield
497.5 mg (100 %). Amorphous, pale yellow solid. 1H NMR
(CDCl3, 500 MHz, 25 °C): δ = 9.47 (s, 1 H, CHO), 8.37 (d, J =
7.9 Hz, 1 H, ArH), 8.12 (dd, J = 7.5, 1.4 Hz, 1 H, ArH), 7.55 (qud,
1
amorphous solid. H NMR (CDCl3, 300 MHz, 25 °C): δ = 9.53 (s,
1 H, CHO), 8.39–8.42 (m, 1 H, ArH), 8.11–8.15 (m, 1 H, ArH), J = 7.5, 1.4 Hz, 2 H, ArH), 7.29–7.32 (m, 2 H, ArH), 7.25 (t, J =
7.57 (qud, J = 7.3, 1.7 Hz, 2 H, ArH), 7.18–7.35 (m, 7 H, ArH), 7.1 Hz, 1 H, ArH), 7.18 (d, J = 7.9 Hz, 1 H, ArH), 7.10–7.15 (m,
6.91–6.97 (m, 2 H, ArH), 5.22 (d, J = 16.4 Hz, 1 H, CHPh AB
system), 5.02 (d, J = 16.4 Hz, 1 H, CHPh AB system), 3.62 (s, 3
H, OCH3) ppm. 13C NMR (CDCl3, 75.5 MHz, 25 °C): δ = 185.7
(CO), 166.1 (CO), 151.0 (C), 137.0 (C), 136.3 (C), 133.0 (ArCH),
132.1 (ArCH), 131.8 (C), 131.0 (ArCH), 130.4 (ArCH), 129.8 (C),
128.9 (2ϫArCH), 127.8 (ArCH), 126.7 (2 ϫArCH), 125.5 (C),
3 H, ArH), 6.87 (d, J = 7.5 Hz, 2 H, ArH), 5.13 (d, J = 16.6 Hz,
1 H, CHPh AB system), 4.97 (d, J = 16.6 Hz, 1 H, CHPh AB
system) ppm. 13C NMR (CDCl3, 75.5 MHz, 25 °C): δ = 186.2
(CO), 169.7 (CO), 151.6 (C), 137.1 (C), 136.1 (C), 133.1 (ArCH),
132.6 (ArCH), 131.7 (ArCH), 131.2 (C), 131.5 (ArCH), 130.0 (C),
128.9 (2ϫArCH), 127.8 (ArCH), 126.7 (2 ϫArCH), 125.4 (C),
124.1 (ArCH), 123.3 (ArCH), 122.2 (ArCH), 116.5 (C), 110.8 124.2 (ArCH), 123.4 (ArCH), 122.2 (ArCH), 116.4 (C), 111.0
(ArCH), 52.6 (OCH ), 48.3 (CH Ph) ppm. FTIR: ν = 1721, 1643,
(ArCH), 48.4 (CH Ph) ppm. FTIR: ν = 1725, 1676, 1354,
˜
˜
3
2
2
1264 cm–1. HRMS (ESI+) calcd. for [C24H19NNaO3]+: 392.1263;
1188 cm–1. HRMS (ESI+) calcd. for [C23H17NNaO3]+: 378.1106;
found 392.1253.
found 378.1113.
2-[1-(Dimethylsulfamoyl-3-formyl-1H-indol-2-yl]benzoic Acid (6c):
Yield 521.4 mg (100%). White foam. H NMR (CDCl3, 500 MHz,
Methyl 2-[1-(Dimethylsulfamoyl)-3-formyl-1H-indol-2-yl]benzoate
(25): A solution of 23 (0.30 g, 1.07 mmol, 1 equiv.) in THF (8 mL)
was added at 0 °C to a suspension of sodium hydride (0.09 g,
2.14 mmol, 60% in oil) in dry THF (8 mL). The reaction mixture
was stirred for 45 min, and N,N-dimethylsulfamoyl chloride
(0.35 mL, 3.2 mmol) was added. The reaction mixture was allowed
to warm to room temperature and left stirring overnight. The sol-
vent was removed in vacuo, and the residue was dissolved in
CH2Cl2 (30 mL) and water (20 mL). The aqueous layer was ex-
tracted with CH2Cl2 (3ϫ10 mL). The combined organic extracts
were dried (MgSO4) and filtered, and the solvents were evaporated.
The resulting brown oil was purified by flash chromatography on
silica gel (heptane/EtOAc, 60:40) to give 25 (0.30 g, 73%) as a white
1
25 °C): δ = 9.46 (s, 1 H, CHO), 8.32–8.35 (m, 1 H, ArH), 8.16 (dd,
J = 7.8, 1.3 Hz, 1 H, ArH), 7.92–7.96 (m, 1 H, ArH), 7.64 (td, J
= 7.5, 1.3 Hz, 1 H, ArH), 7.59 (td, J = 7.5, 1.3 Hz, 1 H, ArH), 7.47
(dd, J = 7.5, 1.3 Hz, 1 H, ArH), 7.36–7.41 (m, 2 H, ArH), 2.53 [s,
6 H, N(CH3)2] ppm. 13C NMR (CDCl3, 75.5 MHz, 25 °C): δ =
187.3 (CO), 170.5 (CO), 149.7 (C), 136.8 (C), 133.6 (ArCH), 132.3
(ArCH), 131.4 (ArCH), 131.1 (C), 130.5 (ArCH), 130.2 (C), 126.0
(ArCH), 125.3 (C), 124.9 (ArCH), 122.1 (ArCH), 119.5 (C), 114.3
(ArCH), 37.8 [N(CH ) ] ppm. FTIR: ν = 2915, 1719, 1385,
˜
3
2
1175 cm–1. HRMS (ESI+) calcd. for [C18H16N2NaO5S]+: 395.0678;
found 395.0732.
1
solid; m.p. 163 °C (heptane/EtOAc). H NMR (CDCl3, 500 MHz,
General Procedure for Ugi 4-CRs. Syntheses of Compounds 7a, 7b,
7d, 7f–7h: The oxo acid (6a–6c, 0.134 mmol, 1 equiv.) and the cor-
responding primary amine 13 (0.134 mmol, 1 equiv.) were dissolved
in methanol (0.85 mL), and the solution was stirred at room tem-
perature for 10 min. Isocyanide (0.134 mmol, 1 equiv.) was added,
and the resulting mixture was heated at 50 °C overnight. Aqueous
HCl solution (0.1 , 1 mL) was added, and the mixture was stirred
for 15 min at room temperature. Water (10 mL) was added, and
the mixture was extracted with CH2Cl2 (3ϫ10 mL). The combined
organic extracts were dried (MgSO4), filtered, and concentrated in
vacuo. The resulting brown oil was purified by flash chromatog-
raphy on silica gel (CH2Cl2/MeOH, 95:5) to give compounds 7a,
7b, 7d, 7f–7h.
25 °C): δ = 9.51 (s, 1 H, CHO), 8.37–8.40 (m, 1 H, ArH), 8.16–
8.21 (m, 1 H, ArH), 8.01–8.04 (m, 1 H, ArH), 7.60–7.66 (m, 2 H,
ArH), 7.48–7.50 (m, 1 H, ArH), 7.37–7.42 (m, 2 H, ArH), 3.69
(s, 3 H, OCH3), 2.65 [s, 6 H, N(CH3)2] ppm. 13C NMR (CDCl3,
75.5 MHz, 25 °C): δ = 187.1 (CO), 166.1 (CO), 150.0 (C), 136.7
(C), 133.3 (ArCH), 132.5 (C), 131.5 (ArCH), 130.8 (ArCH), 130.5
(ArCH), 129.9 (C), 126.0 (ArCH), 125.5 (C), 125.0 (ArCH), 122.2
(ArCH), 119.5 (C), 114.4 (ArCH), 52.8 (OCH3), 38.0 [N(CH3)
] ppm. FTIR: ν = 1721, 1658, 1366, 1172 cm–1. HRMS (ESI+)
˜
2
calcd. for [C19H18N2NaO5S]+: 409.0834; found 409.0873.
General Procedure for Saponification of Indoles 23–25: Aqueous
LiOH (1 , 7.0 mmol, 7 mL, 5 equiv.) was added to a solution of
oxo ester 23, 24, or 25 (1.40 mmol) in THF (9.5 mL), and the mix-
ture was stirred at 60 °C overnight. The mixture was cooled to 0 °C,
aqueous HCl (1 ) was added until pH 2–3, and the resulting mix-
ture was extracted with EtOAc (3ϫ20 mL). The combined organic
extracts were dried (MgSO4) and filtered, and the solvents were
evaporated. The resulting solid was directly used without further
purification.
N,6-Di-tert-Butyl-5-oxo-5,6,7,12-tetrahydroindolo[3,2-d][2]benzazep-
ine-7-carboxamide (7a): Yield 4.3 mg (8 %). White solid; m.p.
1
276 °C (Et2O). H NMR (CDCl3, 500 MHz, 25 °C): δ = 10.02 (s,
1 H, NH), 7.84 (d, J = 7.8 Hz, 1 H, ArH), 7.54 (d, J = 7.8 Hz, 1
H, ArH), 7.51 (d, J = 7.8 Hz, 1 H, ArH), 7.27 (t, J = 7.8 Hz, 1 H,
ArH), 7.17 (t, J = 7.8 Hz, 1 H, ArH), 7.13 (d, J = 7.8 Hz, 1 H,
ArH), 6.96 (t, J = 7.8 Hz, 1 H, ArH), 6.83 (t, J = 7.8 Hz, 1 H,
ArH), 5.58 (s, 1 H, CH), 4.93 (s, 1 H, NH), 1.67 (s, 9 H, tBu), 0.66
(s, 9 H, tBu) ppm. 13C NMR (CDCl3, 75.5 MHz, 25 °C): δ = 170.7
(CO), 168.9 (CO), 137.5 (C), 137.0 (C), 134.9 (C), 132.8 (ArCH),
130.0 (ArCH), 127.4 (ArCH), 127.2 (ArCH), 126.0 (C), 124.3
(ArCH), 123.0 (C), 120.4 (ArCH), 117.5 (ArCH), 114.0 (C), 112.6
(ArCH), 60.0 (CH), 57.7 (C), 51.1 (C), 29.3 (tBu), 28.1 (tBu) ppm.
2-(3-Formyl-1H-indol-2-yl)benzoic Acid (6a): Yield 371.3 mg
(100%). White foam. 1H NMR (MeOD, 500 MHz, 25 °C): δ = 9.56
(s, 1 H, CHO), 8.21 (d, J = 7.3 Hz, 1 H, ArH), 8.13 (dd, J = 7.3,
1.3 Hz, 1 H, ArH), 7.72 (td, J = 7.3, 1.3 Hz, 1 H, ArH), 7.67 (td,
J = 7.3, 1.3 Hz, 1 H, ArH), 7.61 (dd, J = 7.3, 1.3 Hz, 1 H, ArH),
7.44 (d, J = 7.3 Hz, 1 H, ArH), 7.28 (td, J = 7.3, 1.3 Hz, 1 H,
ArH), 7.25 (td, J = 7.3, 1.3 Hz, 1 H, ArH) ppm. 13C NMR (MeOD,
75.5 MHz, 25 °C): δ = 187.6 (CO), 169.7 (CO), 137.9 (C), 134.1
(C), 133.7 (ArCH), 132.9 (ArCH), 132.2 (C), 131.9 (ArCH), 131.2
FTIR: ν = 3183, 1691, 1608, 1597, 1360, 1198, 733 cm–1. HRMS
˜
(ESI+) calcd. for [C25H29N3NaO2]+: 426.2171; found 426.2167.
N-tert-Butyl-6-(4-methoxybenzyl)-5-oxo-5,6,7,12-tetrahydroindolo-
(ArCH), 126.9 (C), 125.0 (ArCH), 123.8 (ArCH), 122.5 (ArCH), [3,2-d][2]benzazepine-7-carboxamide (7b): Yield 36.3 mg (58%).
116.8 (C), 112.8 (ArCH), 112.1 (C) ppm. FTIR: ν = 3187, 1711,
White solid; m.p. 228 °C (Et2O). 1H NMR (CDCl3, 500 MHz,
25 °C): δ = 9.90 (s, 1 H, NH), 7.93 (d, J = 7.9 Hz, 1 H, ArH), 7.45
(d, J = 7.9 Hz, 1 H, ArH), 7.26 (d, J = 7.9 Hz, 1 H, ArH), 7.20 (t,
˜
1686, 1345, 1188 cm–1. HRMS (ESI+) calcd. for [C16H11NNaO3]+:
288.0637; found 288.0650.
5172
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5162–5175

Isocyanide-Based Multicomponent Reactions
J = 7.9 Hz, 1 H, ArH), 7.12–7.16 (m, 3 H, ArH), 7.00 (t, J = 3 H, ArH), 5.69 (m, 1 H, CH), 5.30 (d, J = 17.1 Hz, 1 H, CH),
7.9 Hz, 1 H, ArH), 6.92–6.95 (m, 2 H, ArH), 6.71–6.74 (m, 2 H,
5.17 (d, J = 9.6 Hz, 1 H, CH), 5.11 (s, 1 H, CH), 5.00 (s, 1 H, NH),
ArH), 5.32 (d, J = 14.7 Hz, 1 H, CHPMB AB system), 5.04 (s, 1 4.86 (dd, J = 15.0, 5.3 Hz, 1 H, CH), 4.03 (dd, J = 15.0, 5.3 Hz, 1
H, CH), 4.98 (s, 1 H, NH), 4.72 (d, J = 14.7 Hz, 1 H, CHPMB AB
system), 3.76 (s, 3 H, CH3), 0.68 (s, 9 H, tBu) ppm. 13C NMR
(CDCl3, 75.5 MHz, 25 °C): δ = 169.9 (CO), 168.1 (CO), 159.4
H, CH), 2.32 [s, 6 H, N(CH3)2], 0.83 (s, 9 H, tBu) ppm. 13C NMR
(CDCl3, 75.5 MHz, 25 °C): δ = 169.0 (CO), 166.0 (CO), 139.5 (C),
137.1 (C), 135.7 (C), 133.3 (CH), 130.8 (ArCH), 130.7 (ArCH),
(CO), 137.0 (C), 134.7 (C), 134.5 (C), 132.9 (ArCH), 130.8 (ArCH), 129.6 (ArCH), 129.1 (ArCH), 127.9 (C), 127.5 (C), 126.0 (ArCH),
130.4 (2ϫArCH), 128.5 (C), 128.3 (C), 127.3 (ArCH), 126.4 (C), 124.8 (1 C, ArCH), 119.5 (CH2), 118.3 (ArCH), 117.9 (ArCH), 55.8
125.0 (ArCH), 123.3 (ArCH), 120.3 (ArCH), 117.8 (ArCH), 114.3 (CH), 52.9 (CH2), 51.7 (C), 35.6 [N(CH3)2], 28.2 (tBu) ppm. FTIR:
(2ϫArCH), 113.4 (C), 112.0 (ArCH), 55.6 (CH), 55.5 (CH3), 53.6 ν = 3348, 1673, 1618, 1504, 1373, 750 cm–1. HRMS (ESI+) calcd.
˜
(CH PMB), 51.3 (C), 28.1 (tBu) ppm. FTIR: ν = 3381, 3150, 1686,
for [C26H30N4NaO4S]+: 517.1885; found 517.1884. C26H30N4O4S
(494.61): calcd. C 63.14, H 6.11, N 11.33; found C 62.97, H 6.05,
˜
2
1607, 1504, 1230, 736 cm– 1 . H RM S ( ES I+ ) calcd. for
[C29H29N3NaO3]+: 490.2107; found 490.2133. C29H29N3O3·0.1H2O N 11.26.
(467.56): calcd. C 74.21, H 6.27, N 8.95; found C 73.79, H 5.84, N
N-(tert-Butyl)-6-(2,4-dimethoxybenzyl)-12-(dimethylsulfamoyl)-5-
oxo-5,6,7,12-tetrahydroindolo[3,2-d][2]benzazepine-7-carboxamide
12-Benzyl-N-(tert-butyl)-6-(4-methoxybenzyl)-5-oxo-5,6,7,12-tetra- (7h): Yield 72.1 mg (89%). White solid; m.p. 235 °C (Et2O). 1H
8.82.
hydroindolo[3,2-d][2]benzazepine-7-carboxamide (7d): Yield 44.8 mg
(60 %). White solid; m.p. 248 °C (Et2O). 1H NMR (CDCl3,
500 MHz, 25 °C): δ = 8.06 (d, J = 7.7 Hz, 1 H, ArH), 7.40 (t, J =
NMR (CDCl3, 500 MHz, 25 °C): δ = 8.15 (d, J = 7.9 Hz, 1 H,
ArH), 7.83 (d, J = 7.9 Hz, 1 H, ArH), 7.77 (d, J = 7.9 Hz, 1 H,
ArH), 7.45 (t, J = 7.9 Hz, 1 H, ArH), 7.26–7.41 (m, 5 H, ArH),
7.7 Hz, 1 H, ArH), 7.34 (t, J = 7.7 Hz, 1 H, ArH), 7.26–7.33 (m, 6.40 (s, 1 H, ArH), 6.39 (d, J = 7.9 Hz, 1 H, ArH), 5.36 (s, 1 H,
3 H, ArH), 7.22 (d, J = 7.7 Hz, 1 H, ArH), 7.17–7.20 (m, 2 H,
ArH), 7.12–7.15 (m, 2 H, ArH), 7.02–7.05 (m, 4 H, ArH), 6.67–
6.70 (m, 2 H, ArH), 5.50 (d, J = 17.7 Hz, 1 H, CHBn AB system),
CH), 5.35 (s, 1 H, NH), 5.06 (d, J = 14.2 Hz, 1 H, CHDMB AB
system), 4.76 (d, J = 14.2 Hz, 1 H, , CHDMBAB system), 3.83 (s,
3 H, OCH3), 3.73 (s, 3 H, OCH3), 2.27 [s, 6 H, N(CH3)2], 0.77 (s,
5.45 (d, J = 17.7 Hz, 1 H, CHBn AB system), 5.28 (d, J = 14.3 Hz, 9 H, tBu) ppm. 13C NMR (CDCl3, 75.5 MHz, 25 °C): δ = 169.3
1 H, CHPMB AB system), 5.25 (br. s, 1 H, NH), 5.19 (s, 1 H, CH), (CO), 166.5 (CO), 161.3 (CO), 158.9 (CO), 139.3 (C), 136.5 (C),
4.68 (d, J = 14.3 Hz, 1 H, CHPMB AB system), 3.71 (s, 3 H,
135.4 (C), 132.8 (ArCH), 131.1 (ArCH), 130.1 (ArCH), 129.4
(ArCH), 128.8 (C), 128.5 (ArCH), 127.9 (C), 126.2 (C), 125.6
OCH3), 0.77 (s, 9 H, tBu) ppm. 13C NMR (CDCl3, 75.5 MHz,
25 °C): δ = 169.1 (CO), 167.9 (CO), 159.4 (CO), 138.2 (C), 137.5 (ArCH), 124.4 (ArCH), 118.3 (ArCH), 117.7 (C), 117.6 (ArCH),
(C), 137.1 (C), 136.4 (C), 133.0 (ArCH), 130.6 (ArCH), 130.4 105.1 (ArCH), 99.1 (ArCH), 56.1 (CH), 56.0 (OCH3), 55.6 (OCH3),
(2ϫArCH), 129.2 (2 ϫ ArCH), 128.9 (C), 128.5 (ArCH), 127.8
(ArCH), 127.6 (C), 126.2 (ArCH), 126.0 (C), 125.9 (2ϫArCH),
51.1 (C), 47.2 (CH ), 38.6 [N(CH ) ], 28.0 (tBu) ppm. FTIR: ν =
˜
2 3 2
3415, 1631, 1504, 1174 cm– 1 . HRMS (ESI+ ) calcd. for
123.4 (ArCH), 120.9 (ArCH), 118.1 (ArCH), 115.5 (C), 114.3 [C26H30N4NaO4S]+: 627.2253; found 627.2227.
(2 ϫ ArCH), 111.0 (ArCH), 55.8 (CH), 55.5 (OCH3), 53.1
General Procedure for Ugi 4-CRs. Syntheses of Compounds 7i–7k:
(CH PMB), 51.2 (C), 48.6 (CH Bn), 28.1 (tBu) ppm. FTIR: ν =
˜
2
2
Compound 6c (0.134 mmol, 1 equiv.) and ammonia in EtOH (2 ,
0.134 mmol, 67 µL, 1 equiv.) were dissolved in methanol (0.20 mL),
and the solution was stirred at room temperature for 10 min. Isocy-
anide (0.134 mmol, 1 equiv.) was added, and the resulting mixture
was heated at 50 °C overnight. Aqueous HCl solution (0.1 , 1 mL)
3280, 1665, 1612, 1514 cm– 1 . HRMS (ESI+ ) calcd. for
[C36H35N3NaO3]+: 580.2576; found 580.2578.
N-(tert-Butyl)-12-(dimethylsulfamoyl)-6-(4-methoxybenzyl)-5-oxo-
5,6,7,12-tetrahydroindolo[3,2-d][2]benzazepine-7-carboxamide (7f):
Yield 59.3 mg (77%). White solid; m.p. 169 °C (Et2O). 1H NMR was added, and the mixture was stirred for 15 min at room tem-
(CDCl3, 500 MHz, 25 °C): δ = 8.14 (d, J = 8.4 Hz, 1 H, ArH), 7.88
(dd, J = 7.7, 1.1 Hz, 1 H, ArH), 7.73 (dd, J = 7.7, 1.1 Hz, 1 H,
perature. Water (10 mL) was added, the mixture was extracted with
CH2Cl2 (3ϫ10 mL), and the combined organic extracts were dried
ArH), 7.47 (td, J = 7.7, 1.1 Hz, 1 H, ArH), 7.42 (td, J = 7.7, 1.1 Hz, (MgSO4), filtered, and concentrated in vacuo. The resulting brown
1 H, ArH), 7.30 (td, J = 7.7, 1.1 Hz, 1 H, ArH), 7.18–7.22 (m, 3
H, ArH), 7.10 (d, J = 7.7 Hz, 1 H, ArH), 6.64–6.67 (m, 2 H, ArH),
5.32 (d, J = 14.3 Hz, 1 H, CHPMB AB system), 5.11 (s, 1 H, CH),
5.03 (br. s, 1 H, NH), 4.52 (d, J = 14.3 Hz, 1 H, CHPMB AB
system), 3.67 (s, 3 H, OCH3), 2.26 [s, 6 H, N(CH3)2], 0.78 (s, 9 H,
tBu) ppm. 13C NMR (CDCl3, 75.5 MHz, 25 °C): δ = 169.1 (CO),
166.0 (CO), 159.6 (CO), 139.1 (C), 136.7 (C), 135.5 (C), 130.9
(ArCH), 130.6 (ArCH), 130.4 (2ϫArCH), 129.6 (ArCH), 128.2
(C), 128.9 (ArCH), 128.0 (C), 127.6 (C), 125.8 (ArCH), 125.1 (C),
124.4 (ArCH), 118.0 (ArCH), 117.5 (ArCH), 114.3 (2ϫArCH),
55.8 (CH), 55.5 (CH3), 53.0 (CH2PMB), 51.5 (C), 38.6 [N(CH3)2],
oil was purified by flash chromatography on silica gel (CH2Cl2/
MeOH, 95:5) to give compounds 7i–7k.
N-(tert-Butyl)-12-(dimethylsulfamoyl)-5-oxo-5,6,7,12-tetrahydro-
indolo[3,2-d][2]benzazepine-7-carboxamide (7i): Yield 26.8 mg
1
(44%). White solid; m.p. 154 °C (Et2O). Major rotamer (63%): H
NMR (CDCl3, 500 MHz, 25 °C): δ = 8.22 (d, J = 7.8 Hz, 1 H,
ArH), 7.89 (d, J = 7.8 Hz, 1 H, ArH), 7.78 (d, J = 7.8 Hz, 1 H,
ArH), 7.68 (t, J = 7.8 Hz, 1 H, ArH), 7.54 (d, J = 7.8 Hz, 1 H,
ArH), 7.44 (t, J = 7.8 Hz, 1 H, ArH), 7.38 (t, J = 7.8 Hz, 1 H,
ArH), 7.29 (t, J = 7.8 Hz, 1 H, ArH), 5.55 (s, 1 H, NH), 5.02 (d,
J = 8.2 Hz, 1 H, CH), 2.35 [s, 6 H, N(CH3)2], 0.88 (s, 9 H,
tBu) ppm. 13C NMR (CDCl3, 75.5 MHz, 25 °C): δ = 171.5 (CO),
166.5 (CO), 139.5 (C), 136.8 (C), 133.3 (C), 131.8 (ArCH), 130.3
(ArCH), 130.0 (ArCH), 128.9 (ArCH), 128.5 (C), 128.3 (C), 126.3
28.1 (tBu) ppm. FTIR: ν = 3408, 1703, 1630, 1508, 1381, 1170,
˜
756 cm–1. HRMS (ESI+) calcd. for [C31H34N4NaO5S]+: 597.2148;
found 597.2178.
6-Allyl-N-(tert-butyl)-12-(dimethylsulfamoyl)-5-oxo-5,6,7,12-tetra- (C), 126.1 (ArCH), 125.0 (ArCH), 118.3 (ArCH), 117.9 (ArCH),
hydroindolo[3,2-d][2]benzazepine-7-carboxamide (7g): Yield 55.0 mg
(83 %). White solid; m.p. 219 °C (Et2O). 1H NMR (CDCl3,
500 MHz, 25 °C): δ = 8.23 (d, J = 7.9 Hz, 1 H, ArH), 7.86 (d, J =
7.9 Hz, 1 H, ArH), 7.77 (d, J = 7.9 Hz, 1 H, ArH), 7.54 (d, J =
51.9 (C), 51.0 (CH), 38.7 [N(CH3)2], 28.2 (tBu) ppm. Minor rot-
amer (37%): H NMR (CDCl3, 500 MHz, 25 °C): δ = 8.23 (d, J =
7.8 Hz, 1 H, ArH), 7.91 (d, J = 7.8 Hz, 1 H, ArH), 7.84 (d, J =
7.8 Hz, 1 H, ArH), 7.68 (t, J = 7.8 Hz, 1 H, ArH), 7.58 (d, J =
1
7.9 Hz, 1 H, ArH), 7.50 (t, J = 7.9 Hz, 1 H, ArH), 7.35–7.45 (m, 7.8 Hz, 1 H, ArH), 7.49 (t, J = 7.8 Hz, 1 H, ArH), 7.35 (t, J =
Eur. J. Org. Chem. 2008, 5162–5175
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5173

S. Beaumont, P. Retailleau, P. Dauban, R. H. Dodd
FULL PAPER
7.8 Hz, 1 H, ArH), 7.30 (t, J = 7.8 Hz, 1 H, ArH), 5.69 (s, 1 H,
NH), 4.53 (d, J = 8.2 Hz, 1 H, CH), 2.26 [s, 6 H, N(CH3)2], 1.43
(s, 9 H, tBu) ppm. 13C NMR (CDCl3, 75.5 MHz, 25 °C): δ = 171.4
(CO), 165.6 (CO), 138.7 (C), 136.8 (C), 132.9 (C), 132.0 (ArCH),
129.6 (ArCH), 129.3 (ArCH), 129.2 (ArCH), 128.2 (C), 128.0 (C),
126.1 (C), 125.5 (ArCH), 124.4 (ArCH), 120.0 (ArCH), 117.7
(ArCH), 53.0 (C), 51.7 (CH), 38.5 [N(CH3)2], 28.9 (tBu) ppm.
[C23H26N4NaO4S]+: 477.1572; found 477.1567. C23H26N4O4S·
0.3C4H10O (454.54): calcd. C 60.96, H 6.13, N 11.75; found C
61.08, H 6.27, N 11.41.
General Procedure for Deprotection of Indolobenzazepinones 7. Syn-
theses of Compounds 26–28: A mixture of anisole, trifluorometh-
anesulfonic acid, and trifluoroacetic acid (1:1:10, 1 mL) was added
to one of the indolobenzazepinones 7 (0.051 mmol, 1 equiv.), and
the solution was stirred at room temperature for 1 h. The mixture
was very slowly added to an ice-cold saturated aqueous NaHCO3
solution (20 mL) and extracted with EtOAc (2ϫ10 mL). The com-
bined organic extracts were dried (MgSO4) and filtered, and the
solvents were evaporated. The resulting yellow solid was purified
by flash chromatography on silica gel (CH2Cl2/MeOH, 95:5).
FTIR: ν = 3302, 1643, 1365, 1172 cm–1. HRMS (ESI+) calcd. for
˜
[ C 2 3 H 2 6 N 4 N a O 4 S ] + : 4 7 7 . 1 5 7 2 ; f o u n d 4 7 7 . 1 6 0 3 .
C
23H26N4O4S·0.42 CH2Cl2 (490.21): calcd. C 57.38, H 5.52, N
11.43; found C 57.67, H 5.18, N 11.04.
N-Benzyl-12-(dimethylsulfamoyl)-5-oxo-5,6,7,12-tetrahydroindolo-
[3,2-d][2]benzazepine-7-carboxamide (7j): Yield 32.1 mg (49%).
White, amorphous solid. Major rotamer (57%): 1H NMR (CDCl3,
500 MHz, 25 °C): δ = 8.10–8.23 (m, 2 H, ArH, NH), 7.82 (d, J = N-(tert-Butyl)-6-(4-methoxybenzyl)-5-oxo-5,6,7,12-tetrahydroindolo-
7.7 Hz, 1 H, ArH), 7.69 (d, J = 7.7 Hz, 1 H, ArH), 7.08–7.61 (m,
10 H, ArH), 6.31 (br. t, 1 H, NHBn), 5.17 (d, J = 7.9 Hz, 1 H,
CH), 4.14 (d, J = 15.0 Hz, 1 H, CHPh AB system), 3.94 (d, J =
15.0 Hz, 1 H, CHPh AB system), 2.33 [s, 6 H, N(CH3)2] ppm. 13C
[3,2-d][2]benzazepine-7-carboxamide (26): Yield 20.1 mg (86%).
White solid; m.p. 228 °C (Et2O). 1H NMR (CDCl3, 500 MHz,
25 °C): δ = 9.90 (s, 1 H, NH), 7.93 (d, J = 7.9 Hz, 1 H, ArH), 7.45
(d, J = 7.9 Hz, 1 H, ArH), 7.26 (d, J = 7.9 Hz, 1 H, ArH), 7.20 (t,
NMR (CDCl3, 75.5 MHz, 25 °C): δ = 171.4 (CO), 167.9 (CO), J = 7.9 Hz, 1 H, ArH), 7.12–7.16 (m, 3 H, ArH), 7.00 (t, J =
139.6 (C), 137.4 (C), 132.6 (C), 131.9 (ArCH), 129.6 (C), 129.3 (C), 7.9 Hz, 1 H, ArH), 6.92–6.95 (m, 2 H, ArH), 6.71–6.74 (m, 2 H,
129.2 (C), 129.1 (ArCH), 129.0 (2ϫArCH), 128.6 (ArCH), 128.1
(C), 127.9 (ArCH), 127.5 (2 ϫ ArCH), 126.1 (ArCH), 125.5
(ArCH), 125.1 (ArCH), 118.3 (ArCH), 118.1 (ArCH), 50.6 (CH),
44.0 (CH2), 38.7 [N(CH3)2] ppm. Minor rotamer (43%): H NMR
(CDCl3, 500 MHz, 25 °C): δ = 8.10–8.23 (m, 2 H, ArH, NH), 7.87
(d, J = 7.7 Hz, 1 H, ArH), 7.77 (d, J = 7.7 Hz, 1 H, ArH), 7.08–
ArH), 5.32 (d, J = 14.7 Hz, 1 H, CHPMB AB system), 5.04 (s, 1
H, CH), 4.98 (s, 1 H, NH), 4.72 (d, J = 14.7 Hz, 1 H, CHPMB AB
system), 3.76 (s, 3 H, CH3), 0.68 (s, 9 H, tBu) ppm. 13C NMR
(CDCl3, 75.5 MHz, 25 °C): δ = 169.9 (CO), 168.1 (CO), 159.4
(CO), 137.0 (C), 134.7 (C), 134.5 (C), 132.9 (ArCH), 130.8 (ArCH),
130.4 (2ϫArCH), 128.5 (C), 128.3 (C), 127.3 (ArCH), 126.4 (C),
1
7.61 (m, 10 H, ArH), 6.51 (br. t, 1 H, NHBn), 4.72 (dd, J = 15.0, 125.0 (ArCH), 123.3 (ArCH), 120.3 (ArCH), 117.8 (ArCH), 114.3
5.9 Hz, 1 H, CHPh), 4.67 (d, J = 7.9 Hz, 1 H, CH), 4.48 (dd, J =
(2ϫArCH), 113.4 (C), 112.0 (ArCH), 55.6 (CH), 55.5 (CH3), 53.6
(CH PMB), 51.3 (C), 28.1 (tBu) ppm. FTIR: ν = 3381, 3150, 1686,
15.0, 5.9 Hz, 1 H, CHPh), 2.25 [s, 6 H, N(CH3)2] ppm. 13C NMR
˜
2
(CDCl3, 75.5 MHz, 25 °C): δ = 168.6 (CO), 166.6 (CO), 139.5 (C), 1607, 1504, 1230, 736 cm– 1 . HRMS (ESI+ ) c al cd . for
137.7 (C), 133.4 (C), 130.4 (ArCH), 129.6 (C), 129.3 (C), 129.2 (C), [C29H29N3NaO3]+: 490.2107; found 490.2133.
128.7 (2ϫArCH), 128.5 (ArCH), 128.4 (C), 128.3 (ArCH), 128.0
N-(tert-Butyl)-5-oxo-5,6,7,12-tetrahydroindolo[3,2-d][2]benzazepine-
(2ϫArCH), 127.2 (ArCH), 125.2 (ArCH), 124.7 (ArCH), 124.3
7-carboxamide (27): Yield 12.3 mg (71%). White solid; m.p. 279 °C
(ArCH), 119.5 (ArCH), 117.8 (ArCH), 51.1 (CH), 44.7 (CH2), 38.5
(Et2O). 1H NMR (MeOD, 500 MHz, 25 °C): δ = 8.02 (d, J =
7.9 Hz, 1 H, ArH), 7.75 (d, J = 7.9 Hz, 1 H, ArH), 7.69 (d, J =
7.9 Hz, 1 H, ArH), 7.66 (t, J = 7.9 Hz, 1 H, ArH), 7.48 (d, J =
7.9 Hz, 1 H, ArH), 7.47 (d, J = 7.9 Hz, 1 H, ArH), 7.22 (t, J =
7.9 Hz, 1 H, ArH), 7.19 (t, J = 7.9 Hz, 1 H, ArH), 5.18 (s, 1 H,
CH), 1.07 (s, 9 H, tBu) ppm. 13C NMR (MeOD, 75.5 MHz, 25 °C):
δ = 172.5 (CO), 170.6 (CO), 138.7 (C), 135.8 (C), 134.4 (C), 133.1
(ArH), 133.0 (ArH), 131.4 (C), 128.8 (ArH), 127.3 (ArH), 127.2
(C), 124.2 (ArH), 121.3 (ArH), 119.3 (ArH), 115.4 (C), 113.0
[N(CH ) ] ppm. FTIR: ν = 3352, 1677, 1634, 1379 cm–1. HRMS
˜
3 2
(ESI+) calcd. for [C26H24N4NaO4S]+: 511.1416; found 511.1417.
N-Butyl-12-(dimethylsulfamoyl)-5-oxo-5,6,7,12-tetrahydroindolo-
[3,2-d][2]benzazepine-7-carboxamide (7k): Yield 28.6 mg (47%).
White, amorphous solid. Major rotamer (54%): 1H NMR (CDCl3,
500 MHz, 25 °C): δ = 8.23 (d, J = 7.9 Hz, 1 H, ArH), 7.90 (t, J =
7.9 Hz, 1 H, ArH), 7.76 (d, J = 7.9 Hz, 1 H, ArH), 7.27–7.62 (m,
5 H, ArH), 5.89 (br. t, 1 H, NH), 5.11 (d, J = 8.0 Hz, 1 H, CH),
3.55–3.62 (m, 1 H, CHN), 2.88–2.94 (m, 1 H, CHN), 2.36 [s, 6 H,
N(CH3)2], 1.44–1.53 (m, 2 H, CH2), 0.89 (t, J = 7.3 Hz, 3 H, CH3),
0.80–0.86 (m, 2 H, CH2) ppm. 13C NMR (CDCl3, 75.5 MHz,
25 °C): δ = 171.7 (CO), 167.7 (CO), 139.6 (C), 137.3 (C), 135.1
(C), 131.9 (ArCH), 130.4 (ArCH), 129.6 (ArCH), 129.3 (C), 128.9
(ArCH), 126.1 (ArCH), 125.8 (C), 125.3 (C), 125.1 (ArCH), 119.4
(ArCH), 118.1 (ArCH), 50.5 (CH), 39.8 (CH2), 38.7 [N(CH3)2],
31.6 (CH2), 18.9 (CH2), 13.8 (CH3) ppm. Minor rotamer (46%):
(ArH), 52.6 (C), 28.6 (tBu) ppm. FTIR: ν = 3326, 1675, 1606, 1588,
˜
1591 cm–1. HRMS (ESI+) calcd. for [C21H21N3NaO2]+: 370.1531;
found 370.1509. C21H21N3O2·0.22CH2Cl2 (366.10): calcd. C 69.62,
H 5.90, N 11.48; found C 69.98, H 6.01, N 10.97.
N-(Benzyl)-5-oxo-5,6,7,12-tetrahydroindolo[3,2-d][2]benzazepine-7-
carboxamide (28): Yield 17.7 mg (93%). White foam. 1H NMR
(MeOD, 500 MHz, 25 °C): δ = 8.01 (d, J = 7.8 Hz, 1 H, ArH), 7.72
1H NMR (CDCl3, 500 MHz, 25 °C): δ = 8.12 (d, J = 7.9 Hz, 1 H, (d, J = 7.8 Hz, 1 H, ArH), 7.64 (t, J = 7.8 Hz, 1 H, ArH), 7.63 (d,
ArH), 7.90 (t, J = 7.9 Hz, 1 H, ArH), 7.82 (d, J = 7.9 Hz, 1 H, J = 7.8 Hz, 1 H, ArH), 7.47 (d, J = 7.8 Hz, 1 H, ArH), 7.44 (t, J
ArH), 7.27–7.62 (m, 5 H, ArH), 6.03 (br. t, 1 H, NH), 4.63 (d, J = 7.8 Hz, 1 H, ArH), 7.20 (d, J = 7.8 Hz, 1 H, ArH), 7.06–7.11
= 8.0 Hz, 1 H, CH), 3.29–3.36 (m, 1 H, CHN), 2.74–2.81 (m, 1 H, (m, 4 H, ArH), 6.72–6.76 (m, 2 H, ArH), 5.37 (s, 1 H, CH), 4.27
CHN), 2.26 [s, 6 H, N(CH3)2], 1.27–1.35 (m, 2 H, CH2), 0.81–0.89 (d, J = 15.2 Hz, 1 H, CHBn AB system), 4.11 (d, J = 15.2 Hz, 1
(m, 2 H, CH2), 0.67 (t, J = 7.3 Hz, 3 H, CH3) ppm. 13C NMR H, CHBn AB system) ppm. 13C NMR (MeOD, 75.5 MHz, 25 °C):
(CDCl3, 75.5 MHz, 25 °C): δ = 168.7 (CO), 166.7 (CO), 138.8 (C), δ = 172.1 (CO), 165.6 (CO), 139.6 (C), 138.7 (C), 133.2 (ArH),
136.9 (C), 132.9 (C), 131.8 (ArCH), 130.3 (ArCH), 129.3 (ArCH),
128.5 (C), 128.4 (ArCH), 125.8 (C), 125.5 (ArCH), 124.7 (ArCH),
133.1 (ArH), 131.2 (C), 129.5 (2ϫArH), 128.8 (ArH), 128.1
(2ϫArH), 127.9 (ArH), 127.7 (C), 127.4 (ArH), 124.1 (ArH), 121.4
124.4 (C), 118.4 (ArCH), 117.8 (ArCH), 51.1 (CH), 40.2 (CH2), (ArH), 119.2 (ArH), 114.8 (C), 112.9 (ArH), 51.7 (CH), 44.5
38.6 [N(CH ) ], 31.3 (CH ), 20.2 (CH ), 14.4 (CH ) ppm. FTIR: ν
(CH ) ppm. FTIR: ν = 3328, 1676, 1612, 1590 cm–1. HRMS (ESI+)
˜
˜
3 2
2
2
3
2
= 3289, 1643, 1380, 1172 cm–1. HRMS (ESI+) calcd. for
calcd. for [C24H19N3NaO2]+: 404.1375; found 404.1388.
5174
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5162–5175

Isocyanide-Based Multicomponent Reactions
2005, 70, 1478–1481; d) J. Zhang, A. Jacobson, J. R. Rusche,
W. Herlihy, J. Org. Chem. 1999, 64, 1074–1076.
a) R. G. Linington, D. E. Williams, A. Tahir, R. van Soest,
R. J. Andersen, Org. Lett. 2003, 5, 2735–2738.
a) A. Al Mourabit, P. Potier, Eur. J. Org. Chem. 2001, 237–243;
b) H. Hoffmann, T. Lindel, Synthesis 2003, 1753–1783.
For some recent synthetic studies devoted to the pyrrolo[2,3-c]
azepinone core, see: a) J. Perron, B. Joseph, J.-Y. Mérour, Tetra-
hedron 2003, 59, 6659–6666; b) J. Perron, B. Joseph, J.-Y.
Mérour, Tetrahedron 2004, 60, 10099–10109; c) A. Putey, L.
Joucla, L. Picot, T. Besson, B. Joseph, Tetrahedron 2007, 63,
867–879; d) V. Sharma, T. A. Lansdell, G. Jin, J. J. Tepe, J.
Med. Chem. 2004, 47, 3700–3703.
L. Keller, S. Beaumont, J.-M. Liu, S. Thoret, J. Bignon, J.
Wdzieczak-Bakala, P. Dauban, R. H. Dodd, J. Med. Chem.
2008, 51, 3414–3421.
Application of the Ugi reaction also allows easier access to C-
5-substituted indolo-benzazepinones, since the previous strat-
egy, by a tandem Suzuki coupling/lactamization procedure, re-
quires the synthesis of aminobenzyl o-boronic acids. These are
not easily prepared, nor are they isolated in pure form and with
good yields.
a) D. W. Zaharewitz, R. Gussio, M. Leost, A. M. Senderowitz,
T. Lahusen, C. Kunick, L. Meijer, E. A. Sausville, Cancer Res.
1999, 59, 2566–2569; b) C. Schultz, A. Link, M. Leost, D. W.
Zaharewitz, R. Gussio, E. A. Sausville, L. Meijer, C. Kunick,
J. Med. Chem. 1999, 42, 2909–2919.
T. Sakamoto, T. Nagano, Y. Kondo, H. Yamanaka, Chem.
Pharm. Bull. 1988, 36, 2248–2252.
P.-E. Broutin, F. Colobert, Eur. J. Org. Chem. 2005, 1113–1128.
F. K. Rosendahl, I. Ugi, Justus Liebigs Ann. Chem. 1963, 666,
65–67.
T. A. Keating, R. W. Armstrong, J. Am. Chem. Soc. 1996, 118,
2574–2583.
Whereas deprotected indolo-benzazepinone 18 inhibits tubulin
polymerization with an IC50 of 6.2 µ, its tert-butyl precursor
5h displays a more potent inhibitory activity of 1.8 µ, com-
parable with that of colchicine (2.2 µ).
Deprotection of the N-(Boc)indole derivative 21 was found to
be necessary since the Vilsmeier–Haack reaction only occurred
with the free NH compound.
The presence of a Boc or SO2Ph group on the indole nitrogen
proved to be incompatible with the basic conditions used to
generate the carboxylic acid, in contrast to the use of the benzyl
and the dimethylsulfamoyl groups.
No satisfactory explanation for the lack of reactivity observed
during the reaction between indoles 6, tert-butylamine 13g, and
tert-butyl isocyanide 14g has so far been found.
Acknowledgments
[8]
We thank the Institut de Chimie des Substances Naturelles (S. B.)
for a fellowship.
[9]
[1] a) Multicomponent reactions (Eds.: J. Zhu, H. Bienaymé),
Wiley-VCH, Weinheim, 2005; b) D. J. Ramón, M. Yus, Angew.
Chem. 2005, 117, 1628–1661; Angew. Chem. Int. Ed. 2005, 44,
1602–1634.
[2] For reviews, see: a) A. Dömling, Chem. Rev. 2006, 106, 17–89;
b) L. Banfi, R. Riva, Org. React. 2005, 65, 1–140; c) J. Zhu,
Eur. J. Org. Chem. 2003, 1133–1144; d) A. Dömling, I. Ugi,
Angew. Chem. 2000, 112, 3300–3344; Angew. Chem. Int. Ed.
2000, 39, 3168–3210.
[10]
[11]
[12]
[3] a) I. Ugi, R. Meyr, U. Fetzer, C. Steinbruckner, Angew. Chem.
1959, 71, 386; b) S. Marcaccini, T. Torroba, Nature Protocols
2007, 2, 632–639.
[4] For recent examples, see: a) J. D. Sunderhaus, C. Dockendorff,
S. F. Martin, Org. Lett. 2007, 9, 4223–4226; b) L. Banfi, A.
Basso, G. Guanti, N. Kielland, C. Repetto, R. Riva, J. Org.
Chem. 2007, 72, 2151–2160; c) L. El Kaïm, L. Grimaud, J.
Oble, J. Org. Chem. 2007, 72, 5835–5838; d) L. El Kaïm, M.
Gizolme, L. Grimaud, J. Oble, Org. Lett. 2006, 8, 4019–4021;
e) F. Bonnaterre, M. Bois-Choussy, J. Zhu, Org. Lett. 2006, 8,
4351–4354.
[5] a) See ref. 2a; pp. 56–68; b) I. Akritopoulou-Zanze, Curr. Opin.
Chem. Biol. 2008, 12, 324–331; c) L. Weber, Curr. Med. Chem.
2002, 9, 2085–2093; d) O. E. Vercillo, C. K. Z. Andrade, L. A.
Wessjohann, Org. Lett. 2008, 10, 205–208; e) H. Habashita, M.
Kobuko, S.-I. Hamano, N. Hamanaka, M. Toda, S. Shibay-
ama, H. Tada, K. Sagawa, D. Fukushima, K. Maeda, H. Mits-
uya, J. Med. Chem. 2006, 49, 4140–4152; f) A. D. Borthwick,
D. E. Davies, A. M. Exall, R. J. D. Hatley, J. A. Hughes, W. R.
Irving, D. G. Livermore, S. L. Sollis, F. Nerozzi, K. L. Valko,
M. J. Allen, M. Perren, S. S. Shabbir, P. M. Woollard, M. A.
Price, J. Med. Chem. 2006, 49, 4159–4170.
[6] a) C. G. Gilley, M. J. Buller, Y. Kobayashi, Org. Lett. 2007, 9,
3631–3634; b) D. Michalik, A. Schaks, L. A. Wessjohann, Eur.
J. Org. Chem. 2007, 149–157; c) K. Rikimaru, K. Mori, T. Kan,
T. Fukuyama, Chem. Commun. 2005, 394–396; d) A. Endo, A.
Yanagisawa, M. Abe, S. Tohma, T. Kan, T. Fukuyama, J. Am.
Chem. Soc. 2002, 124, 6552–6554; e) P. Cristau, J.-P. Vors, J.
Zhu, Tetrahedron 2003, 59, 7859–7870; f) B. Beck, S. Hess, A.
Dömling, Bioorg. Med. Chem. Lett. 2000, 10, 1701–1705.
[7] a) A. Dömling, Amino Group Chemistry, From Synthesis to the
Life Sciences (Ed.: A. Ricci), Wiley-VCH, Weinheim, 2008,
p. 149–183; b) A. P. Ilyn, M. L. Loseva, V. Y. Vvedensky, E. B.
Putsykina, S. E. Tkachenko, D. V. Kravchenko, A. V. Khvat,
M. Y. Krasavin, A. V. Ivachtchenko, J. Org. Chem. 2006, 71,
2811–2819; c) A. P. Ilyn, A. S. Trifilenkov, J. A. Kuzovkova,
S. A. Kutepov, A. V. Nikitin, A. V. Ivachtchenko, J. Org. Chem.
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
A. Batch, R. H. Dodd, J. Org. Chem. 1998, 63, 872–877.
Received: June 30, 2008
Published Online: September 16, 2008
Eur. J. Org. Chem. 2008, 5162–5175
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5175