Post ugi gold(I)- and platinum(II)-catalyzed alkyne activation: Synthesis of diversely substituted fused azepinones and pyridinones

Article abstract of DOI:10.1055/s-0033-1339474

A post-Ugi late-transition-metal-catalyzed intramolecular hydroarylation approach opens a new gateway for the synthesis of diversely substituted pyrrolopyridinones, pyrroloazepinones thiophenoazepinones, azepinoindoles, and azepinobenzothiophenes applying mild reaction conditions. A detailed investigation of the scope of this strategy is discussed. Georg Thieme Verlag Stuttgart New York. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1339474

PAPER
▌2571
paper
Post Ugi Gold(I)- and Platinum(II)-Catalyzed Alkyne Activation: Synthesis of
Diversely Substituted Fused Azepinones and Pyridinones
Gold(I)- and Platinum(II)-Catalyzed Alkyne Activation
Amit Kumar,a,b Dipak D. Vachhani,a Sachin G. Modha,*a,c Sunil K. Sharma,b Virinder S. Parmar,b
Erik V. Van der Eycken*a
a
Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, KU Leuven, Celestijnenlaan 200F,
3001 Leuven, Belgium
Fax +32(16)327990; E-mail: erik.vandereycken@chem.kuleuven.be
b
Bioorganic Laboratory, Department of Chemistry, University of Delhi, Delhi-110 007, India
c
Present address: ‘Mani Bhuvan’, Nr. Lohana Mahajan Vadi, Chhaya-360 578, Porbandar, Gujarat, India
E-mail: sachinmodha@gmail.com
Received: 02.05.2013; Accepted after revision: 01.07.2013
ducts 5a–d in good to excellent yields. These compounds
Abstract: A post-Ugi late-transition-metal-catalyzed intramolecu-
were subjected to our previously developed conditions for
lar hydroarylation approach opens a new gateway for the synthesis
intramolecular hydroarylation. Upon reaction with
Au(PPh3)OTf in chloroform at 50 °C for three hours, the
of diversely substituted pyrrolopyridinones, pyrroloazepinones
thiophenoazepinones, azepinoindoles, and azepinobenzothiophenes
applying mild reaction conditions. A detailed investigation of the corresponding pyrrolopyridinones 6a–d were obtained in
scope of this strategy is discussed.
good yields (Table 1) via exo-dig cyclization of the pyr-
role on the internal alkyne followed by rearrangement.
Remarkably even in the presence of an indole substituent,
the intramolecular hydroarylation takes place on the pyr-
role ring, clearly showing the higher nucleophilicity of the
latter11 (Table 1, entry 3, 6c).
Key words: gold, platinum, alkyne, Ugi, azepinone, pyridinone
Azepines fused with an aryl or heteroaryl subunit repre-
sent a widely studied class of biologically interesting
medium-sized ring systems.1 A plethora of literature is
available for the construction of these heterocyclic sys-
tems employing various multistep synthetic sequences.2
Although these approaches are useful for the construction
of specific molecules, a general highly chemo-, regio-,
and stereoselective methodology is desirable. Recent de-
velopments in transition-metal-catalyzed alkyne activa-
tion have opened the way for the synthesis of various
carbocycles and heterocycles.3 Compared to other transi-
tion metals, the selectivity of gold and platinum catalysts
towards alkyne activation, is remarkable.4,5 Although suc-
cessful, most strategies lack the aspect of diversity. One of
the best ways to address this is the application of
multicomponent6–8 reactions allowing the introduction of
various functional groups in one step.
Reaction of Ugi adducts 5a–d with PtCl2 in chloroform at
50 °C for 14 hours resulted in the formation of the pyrro-
loazepinones 7 as the major product (Table 1). This 7-
membered fused ring system is formed via an endo-dig
cyclization of the pyrrole on the internal alkyne, followed
by rearrangement.10 The cationic nature of the gold in
Au(PPh3)OTf, activates the alkyne to a larger extent com-
pared to PtCl2 allowing the pyrrole ring to attack quickly.
This is why the reaction time, in the case of Au(PPh3)OTf,
is shorter compared to PtCl2. The presence of an indole
substituent seems to inhibit the cyclization (Table 1, entry
3).
After these interesting observations on pyrrole we were
keen to extend this methodology to the readily available
2-formylthiophene, 2-formylindole, and 2-formylbenzo-
thiophene. The Ugi-4CR of 2-formylthiophene (8a) with
p-methoxybenzylamine (2d), but-2-ynoic acid (3a), and
tert-butyl isonitrile (4b) in methanol at 50 °C delivers the
Ugi adduct 9a in 86% yield. This compound when treated
with Au(PPh3)OTf (5 mol%) in chloroform, did not react
even after 24 hours, and only starting material was recov-
ered (Scheme 2).
Our group, which is dedicated to the development of new
diversity-oriented methodologies based on transition-
metal catalysis and multicomponent reactions, has report-
ed various approaches for the synthesis of biologically in-
teresting heterocycles.9 Inspired by our latest findings on
the post-Ugi gold-catalyzed synthesis of pyrrolopyridi-
nones and on the platinum-catalyzed synthesis of pyrro-
loazepinones,10 we performed a detailed study of the
scope of these protocols employing different heterocycles
such as pyrrole, thiophene, benzothiophene, and indole
(Scheme 1).
In contrast, when the same Ugi adduct 9a was subjected
to PtCl2 (5 mol%) in chloroform, the expected thiopheno-
azepinone was formed in 58% yield (Scheme 2).
The proposed mechanism for the formation of the thio-
phenoazepinone is depicted in Scheme 3. The nucleophil-
ic C2-position of the thiophene5h attacks on the
platinum(II)-activated alkyne in an endo-dig fashion giv-
ing rise to the spiro intermediate B. This intermediate un-
dergoes a 1,2-shift followed by deprotonation and
Ugi-4CR of 2-formylpyrrole 110 with amine 2, alkynoic
acid 3, and isonitrile 4 in methanol at 50 °C gives Ugi ad-
SYNTHESIS 2013, 45, 2571–2582
Advanced online publication: 01.08.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1339474; Art ID: SS-2013-Z0332-OP
© Georg Thieme Verlag Stuttgart · New York

2572
A. Kumar et al.
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previous work:
R3
R3
R3
O
X = NR4
O
O
cat. Au(I)
cat. Pt(II)
N
R1
N
R1
endo-
selective
N
N
exo-
selective
R1
NH
R2
N
R4
N
R4
NH
R2
R4
O
NH
O
O
R2
this work:
R3
R3
O
O
cat. Pt(II)
N
N
R1
S
R1
endo-selective
S
O
NH
R2
NH
O
R2
R3
R3
O
O
cat. Au(I)
N
endo-selective
N
R1
NH
R2
R1
X
X
O
O
NH
R2
X = S, NR4
Scheme 1 Comparison of this work with our previous report
protodeplatination to form the thiophenoazepinone 11a and azepinobenzothiophenes 17a,b, respectively (Table
(Scheme 3).
2). As is evident from the examples in Table 2 various
substituents are compatible with this protocol. A bulky
substituent like a phenyl group is well tolerated on the al-
kyne and delivers the corresponding azepinones in excel-
lent yields (Table 2, entries 3, 4, 6, and 9). These examples
also discard the possibility of nucleophilic attack from
2nd position because the spiro intermediate formation in
the presence of a phenyl substituent would be sterically
unfavored in such a mild reaction condition. Ugi adducts
14 and 15 did not give any cyclized product upon treat-
ment with PtCl2, and only starting material was recovered.
This observation clearly shows that PtCl2 is not effective
for the less nucleophilic indole and benzothiophene ring
systems.
The Ugi-4CR of 2-formylindole (12a) and 2-formylben-
zothiophene (13a) with amine 2, alkynoic acid 3, and iso-
nitrile 4 in methanol at 50 °C gives the corresponding Ugi
adducts 14a–g and 15a,b in good to excellent yields. As
the nucleophilicity of indole and benzothiophene is lower
compared to that of pyrrole and thiophene, we were keen
to know the effect of gold(I) and platinum(II) catalysis on
the obtained Ugi adducts 14 and 15. Upon treatment of
these compounds with Au(PPh3)OTf (5 mol%) in chloro-
form, only 7-membered ring formation was observed via
endo-dig attack of the aromatic ring on the activated al-
kyne resulting in the formation of azepinoindoles 16a–g
O
Au(PPh3)OTf (5 mol%)
CHCl3, 50 °C, 24 h
N
PMB
O
S
PMB
CHO
S
H2N
MeOH
50 °C, 48 h
NH
O
N
8a
PMB
2d
NC
S
+
10a, 0%
COOH
NH
O
O
3a
9a
4b
PtCl2 (5 mol%)
CHCl3, 50 °C, 14 h
N
PMB = p-methoxybenzyl
PMB
S
NH
O
11a, 58%
Scheme 2 Post-Ugi PtCl2-catalyzed synthesis of thiophenoazepinones
Synthesis 2013, 45, 2571–2582
© Georg Thieme Verlag Stuttgart · New York

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Gold(I)- and Platinum(II)-Catalyzed Alkyne Activation
2573
Table 1 Regioselective Synthesis of Pyrrolopyridinones and Pyrroloazepinones
R3
R3
R3
O
O
CHO
R2
H2N
Au(PPh3)OTf (5 mol%)
CHCl3, 50 °C, 3 h
or
N
R1
O
MeOH
50 °C, 48 h
1
N
N
R2
N
or
R2
2
+
N
R2
N
R1
N
R1
PtCl2 (5 mol%)
CHCl3, 50 °C, 14 h
COOH
NC
R4
R1
NH
R4
NH
R4
O
NH
R4
O
O
3
6
7
5
4
R3
Entry
Ugi adduct 5a
Pyrrolopyridinones 6a (conditions A)b
Pyrroloazepinone 7a (conditions B)c
H
O
O
O
N
N
N
N
N
N
Me
1
Me
Me
NH
HN
O
O
NH
O
5a (73%)
7a (79%)
6a (62%)
H
O
N
O
O
N
N
N
N
2
Me
O
N
Me
HN
NH
O
NH
O
Me
5b (86%)
7b (82%)
6b (76%)
H
O
O
O
NH
N
N
N
N
N
N
3
Me
O
Me
O
NH
NH
NH
Me
O
NH
N
H
5c (56%)
7c (0%)d
6c (60%)
OMe
H
N
O
O
N
OMe
O
OMe
N
N
N
4
NH
O
N
NH
NH
O
O
7d (60%)e
6d (84%)
5d (73%)
a Yields are isolated yields.
b Conditions A: reactions were run on a 0.25 mmol scale of 5 with AuPPh3Cl (5 mol%), AgOTf (5 mol%), and CHCl3 (2 mL) in a screw capped
vial at 50 °C for 3 h.
c Conditions B: reactions were carried on a 0.25 mmol scale of 5 with PtCl2 (5 mol%) and CHCl3 (2 mL) in a screw capped vial at 50 °C for 14 h.
d No product was formed even after 24 h; only starting 5c was recovered.
e Also 25% of 6d was formed as a minor product, employing conditions B.
© Georg Thieme Verlag Stuttgart · New York
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A. Kumar et al.
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Table 2 Synthesis of Azepinoindoles and Azepinobenzothiophenes via Post-Ugi Au(I)-Catalyzed Intramolecular Hydroarylation
R2
X
R1
H2N
R2
COOH
O
2
Au(PPh3)OTf (5 mol%)
CHCl3, 50 °C, 3 h
MeOH
50 °C, 48 h
O
3
N
R1
N
R2
NC
CHO
+
R1
X
X
O
NH
R3
NH
R3
O
12a, X = NH, NMe
13a, X = S
R3
4
14a–g, X = NH, NMe
15a–b, X = S
16a–g, X = NH, NMe
17a–b, X = S
Entry
Ugi adducts 14 and 15a
Compounds 16 and 17a,b
OMe
OMe
O
O
N
N
N
1
H
NH
N
H
O
O
HN
16a (81%)
14a (75%)
OMe
OMe
O
O
N
N
N
H
NH
2
O
N
H
O
HN
16b (90%)
14b (48%)
OMe
OMe
O
O
N
N
3
N
H
N
H
NH
O
NH
O
16c (88%)
14c (88%)
OMe
OMe
MeO
OMe
O
O
N
4
N
N
H
NH
O
N
H
NH
O
16d (85%)
14d (69%)
Synthesis 2013, 45, 2571–2582
© Georg Thieme Verlag Stuttgart · New York

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Gold(I)- and Platinum(II)-Catalyzed Alkyne Activation
2575
Table 2 Synthesis of Azepinoindoles and Azepinobenzothiophenes via Post-Ugi Au(I)-Catalyzed Intramolecular Hydroarylation (continued)
R2
X
R1
H2N
R2
COOH
O
2
Au(PPh3)OTf (5 mol%)
CHCl3, 50 °C, 3 h
MeOH
50 °C, 48 h
O
3
N
R1
N
R2
NC
CHO
+
R1
X
X
O
NH
R3
NH
R3
O
12a, X = NH, NMe
13a, X = S
R3
4
14a–g, X = NH, NMe
15a–b, X = S
16a–g, X = NH, NMe
17a–b, X = S
Entry
Ugi adducts 14 and 15a
Compounds 16 and 17a,b
O
O
N
N
N
H
5
NH
O
O
N
H
HN
16e (92%)
14e (77%)
O
O
N
6
N
H
N
NH
O
N
H
NH
O
16f (79%)
14f (53%)
OMe
OMe
O
O
N
N
N
7
NH
N
O
O
HN
16g (83%)
14g (76%)
OMe
OMe
O
O
N
N
S
8
NH
S
O
O
HN
17a (80%)
15a (70%)
© Georg Thieme Verlag Stuttgart · New York
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A. Kumar et al.
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Table 2 Synthesis of Azepinoindoles and Azepinobenzothiophenes via Post-Ugi Au(I)-Catalyzed Intramolecular Hydroarylation (continued)
R2
X
R1
H2N
R2
COOH
O
2
Au(PPh3)OTf (5 mol%)
CHCl3, 50 °C, 3 h
MeOH
50 °C, 48 h
O
3
N
R1
N
R2
NC
CHO
+
R1
X
X
O
NH
R3
NH
R3
O
12a, X = NH, NMe
13a, X = S
R3
4
14a–g, X = NH, NMe
15a–b, X = S
16a–g, X = NH, NMe
17a–b, X = S
Entry
Ugi adducts 14 and 15a
Compounds 16 and 17a,b
OMe
OMe
O
O
N
9
N
S
NH
O
S
NH
O
17b (91%)
15b (95%)
a Yields are isolated yields.
b All the reactions were run on a 0.25 mmol scale of 14 or 15 with AuPPh3Cl (5 mol%), AgOTf (5 mol%), and CHCl3 (2 mL) in a screw capped
vial at 50 °C for 3 h.
The proposed mechanism for the formation of azepinoin- pyridinones and azepinones. The diversity introduced via
doles and azepinobenzothiophenes is shown in the Ugi reaction, the regioselectivity assured by the gold(I) or
Scheme 4. Direct attack of the nucleophilic C3-position of platinum(II) catalysis during ring closure, and the mild re-
the heterocyclic ring5h on the activated alkyne occurs in an action conditions are the merits of these protocols.
endo-dig fashion resulting in the formation of intermedi-
ate B. Subsequent deprotonation and protodeauration re-
sults in the formation of the corresponding azepinones 16
and 17 (Scheme 4).
The 1H (300 or 400 MHz) and 13C (75 or 100 MHz) chemical shifts
are reported in parts per million relative to TMS using the residual
solvent signal as the internal reference. Standard abbreviations were
used to designate chemical shift multiplicities. The 13C NMR spec-
tra are proton decoupled. The melting points were determined on a
digital apparatus and are uncorrected. High-resolution mass spectra
were recorded by using double-focusing magnetic sector and at an
ion source temperature of 150–250 °C, as required. High-resolution
EI-mass spectra were performed with a resolution of 10 000. Alde-
hyde 1b was synthesized according to a known literature proce-
dure.13 The reagents and catalysts were purchased from commercial
sources and used as such. Reactions were typically run in oven-
dried screw-cap vial under inert atmosphere.
Although we have no hard proof regarding the mecha-
nisms to explain the different outcome of the reactions,
the results might be interpreted as follows. According to
the literature, pyrrole5a,10 and thiophene5h,x,y,12 perform nu-
cleophilic attack preferably via the second position and
thus 5- or 6- membered spiro intermediates are obvious in
our case. Apart from the nucleophilicity of the substrate,
the steric bulk of the catalyst might be playing a crucial
role. In comparison, Au(PPh3)OTf is bulkier than PtCl2,
thus it prefers an exo-dig attack to avoid steric hindrance
in the spiro intermediate stage. This hypothesis is support-
ed by the fact that AuCl or AuCl3 gives only endo-dig cy-
clization.10 So in the case of five- or six-membered spiro
intermediate pathways Au(PPh3)OTf forms the exo-dig
product while PtCl2 forms the endo-dig compound. On the
contrary, indole9b,c and benzothiophene prefer attack via
its third position and will not form a spiro intermediate,
thus allowing the Au(PPh3)OTf to produce the endo-dig
product.
Ugi Products 5a–d; General Procedure
To a solution of pyrrole-2-carbaldehyde 1a,b (2 mmol) in MeOH (3
mL) were added successively Na2SO4 (0.3 g), the appropriate amine
2a–d (1.2 equiv), acid 3a (1.2 equiv), and isonitrile 4a,b (1.2 equiv)
in a screw capped vial equipped with a magnetic stir bar. The reac-
tion mixture was stirred at 50 °C for 24–48 h in a closed vial. After
completion of the reaction (as indicated on TLC), the mixture was
diluted with EtOAc (100 mL) and extracted with H2O (50 mL). The
organic layer was washed with brine (50 mL), dried (MgSO4) and
evaporated under reduced pressure to obtain a residue, which was
subjected to silica gel column chromatography (50% EtOAc in hep-
tane) to afford the desired products 5a–d (Table 1).
In conclusion, we have elaborated post-Ugi gold(I)- and
platinum(II)-catalyzed intramolecular hydroarylation ap- 2-oxoethyl]but-2-ynamide (5a)
proaches for the synthesis of diversely substituted fused
N-Benzyl-N-[2-(tert-butylamino)-1-(1-methyl-1H-pyrrol-2-yl)-
Yield: 534 mg (73%); white solid, mp 167–169 °C; rotameric ratio
~1:3.
Synthesis 2013, 45, 2571–2582
© Georg Thieme Verlag Stuttgart · New York

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Gold(I)- and Platinum(II)-Catalyzed Alkyne Activation
2577
R2
[Au]
O
N
O
R1
Bn
N
N
1,2 shift
X
O
NH
NH
O
14, X = NH, NMe
15, X = S
R3
B'
[Au]
O
R2
H
O
O
[Au+]
[Au+I]
N
C
N
N
Bn
R1
R2
[Au+I]
X
[Au+]
NH
NH
R3
H+
O
O
C'
O
H+
N
Bn
16, X = NH, NMe
17, X = S
N
N
R1
R2
[Au]
X
A'
NH
H
N
H
O
[Au+I]
O
NH
R3
O
A
O
N
R1
X = NMe
X
N
Bn
NH
R3
O
B
O
R
O
NH
N
Scheme 4 Proposed mechanism for the formation of azepinoindoles
and azepinobezothiophenes
6a
X
NH
O
9a
123.3, 111.6, 111.4, 107.5 (2), 91.2, 90.4, 74.1, 73.3, 60.1, 53.7,
51.7, 50.5, 46.3, 33.2, 33.1, 28.6, 28.5, 28.4, 4.1.
X = NMe, S
O
HRMS: m/z calcd for C22H27N3O2: 365.2103; found: 365.2121.
N
X
[Pt+II
]
PMB
N-[2-(tert-Butylamino)-1-(1-methyl-1H-pyrrol-2-yl)-2-oxoeth-
yl]-N-pentylbut-2-ynamide (5b)
Yield: 594 mg (86%); yellow solid; mp 169–171 °C.
[Pt+II
]
O
O
NH
11a
1H NMR (300 MHz, CDCl3): δ = 6.64 (br s, 1 H), 6.32 (br s, 1 H),
6.15 (s, 1 H), 6.09 (br s, 1 H), 5.71 (br s, 1 H), 3.57–3.32 (m, 5 H),
1.99 (s, 3 H), 1.38–1.34 (m, 10 H), 1.19–1.03 (m, 4 H), 0.78 (t,
J = 7.07 Hz, 3 H), 0.54–0.50 (m, 1 H).
13C NMR (75 MHz, CDCl3): δ = 167.0, 155.4, 125.5, 123.3, 111.3,
107.7, 89.1, 73.6, 52.7, 51.7, 47.0, 33.7, 28.9, 28.7, 28.6, 28.4, 21.8,
13.8, 4.0.
N
PMB
H+
X
A
[Pt+I]
NH
O
H
O
O
[Pt+II
]
N
X
PMB
HRMS: m/z calcd for C20H31N3O2: 345.2416; found: 345.2388.
NH
C
[Pt+I]
N
N-[2-(1H-Indol-3-yl)ethyl]-N-[2-(tert-butylamino)-1-(1-methyl-
1H-pyrrol-2-yl)-2-oxoethyl]but-2-ynamide (5c)
Yield: 469 mg (56%); off-white solid; mp 177–179 °C; rotameric
ratio ~1:9.
1H NMR (300 MHz, CDCl3): δ = 7.98 (br s, 1 H), 7.47 (d, J = 7.75
Hz, 1 H), 7.31 (d, J = 8.15 Hz, 1 H), 7.14 (t, J = 7.56 Hz, 1 H), 7.05
(t, J = 7.26 Hz, 1 H), 6.88 (br s, 0.11 H), 6.81 (d, J = 1.98 Hz, 0.87
H), 6.72 (br s, 1 H), 6.44 (d, J = 3.47 Hz, 0.90 H), 6.29 (br s, 0.11
H), 6.21–6.19 (m, 1.82 H), 5.69 (br s, 1 H), 3.86–3.76 (m, 1 H),
3.71–3.60 (m, 1.44 H), 3.56 (s, 2.59 H), 2.88–2.79 (m, 0.98 H), 2.05
(s, 0.29 H), 2.02–1.96 (m, 3.71 H), 1.35 (s, 9 H).
O
1,2 shift
PMB
X
NH
O
PMB = p-methoxybenzyl
B
Scheme 3 Proposed mechanism for the formation of pyrrolopyridi-
none, pyrroloazepinone and thiophenoazepinone
13C NMR (75 MHz, CDCl3): δ = 167.1, 155.5, 136.2, 127.2, 125.6,
123.7, 122.1, 121.7, 118.9, 118.5, 112.6, 111.5, 111.2, 107.9, 89.3,
73.6, 53.1, 51.7, 47.9, 33.7, 28.6 (2), 25.0, 3.9.
1H NMR (300 MHz, CDCl3): δ = 7.12 (m, 3 H), 6.87 (m, 1.81 H),
6.66 (m, 0.22 H), 6.26 (m, 1.78 H), 6.10 (m, 0.24 H), 5.98 (m, 1.74
H), 5.90 (0.22 H), 5.60 (br s, 0.72 H), 5.48 (br s, 0.19 H), 5.11 (d,
J = 15.91 Hz, 0.73 H), 4.51 (d, J = 15.91 Hz, 1.26 H), 4.33 (d,
J = 14.91 Hz, 1.26 H), 3.12 (s, 0.71 H), 3.00 (s, 2.27 H), 2.02–1.98
(m, 3 H), 1.33–1.27 (m, 9 H).
HRMS: m/z calcd for C25H30N4O2: 418.2369; found: 418.2335.
N-[1-(1-Benzyl-1H-pyrrol-2-yl)-2-(cyclohexylamino)-2-oxoeth-
yl]-N-(4-methoxybenzyl)but-2-ynamide (5d)
Yield: 726 mg (73%), white solid; mp 130–131 °C; rotameric ratio
~1:2.
13C NMR (75 MHz, CDCl3): δ = 167.3, 167.3, 156.1, 137.8, 137.5,
129.2, 128.5, 128.0, 127.8, 127.6, 127.2, 126.8, 126.4, 124.9, 123.7,
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2571–2582

2578
A. Kumar et al.
PAPER
HRMS: m/z calcd for C25H30N4O2: 418.2369; found: 418.2362.
1H NMR (300 MHz, CDCl3): δ = 7.31–7.23 (m, 3 H), 6.98–6.82 (m,
4 H), 6.73–6.70 (m, 2.36 H), 6.64 (br s, 0.40 H), 6.49 (br s, 0.62 H),
6.37 (br s, 0.63 H), 6.28 (br s, 0.44 H), 6.21 (t, J = 3.24 Hz, 0.36 H),
6.09 (t, J = 3.24 Hz, 0.61 H), 5.87 (s, 0.63 H), 5.79 (s, 0.32 H), 5.24–
5.14 (m, 1 H), 4.86 (d, J = 16.05 Hz, 0.66 H), 4.70–4.66 (m, 1.34
H), 4.52–4.23 (m, 2 H), 3.76–3.75 (m, 3 H), 3.70–3.63 (m, 1 H),
1.95 (s, 2 H), 1.86–1.70 (m, 3 H), 1.61–1.51 (m, 4 H), 1.32–1.23 (m,
2 H), 1.00–0.81 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 167.3, 167.1, 158.7, 158.5, 155.9,
155.5, 137.5, 137.3, 130.4, 130.3, 129.9, 128.9 (2), 128.8 (2), 128.7,
127.7 (2), 126.8, 126.6 (2), 124.8, 124.7, 123.9, 123.2, 113.5, 113.4,
112.5, 112.4, 108.0, 107.9, 90.9, 90.2, 74.1, 73.0, 59.5, 55.2 (2),
53.6, 50.5, 50.2, 49.8, 48.4, 48.3, 45.6, 32.6, 32.5, 32.4, 25.4 (2),
24.6 (2), 4.1, 3.9.
(E)-1-Benzyl-N-cyclohexyl-4-ethylidene-6-(4-methoxybenzyl)-
5-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-7-carbox-
amide (6d)
Yield: 105 mg (84%); white solid; mp 134–135 °C.
1H NMR (300 MHz, CDCl3): δ = 7.18–7.16 (m, 3 H), 7.04 (d,
J = 8.46 Hz, 2 H), 6.97–6.87 (m, 3 H), 6.71–6.68 (m, 3 H), 6.40 (d,
J = 2.88 Hz, 1 H), 5.58 (d, J = 8.01 Hz, 1 H), 5.52–5.43 (m, 2 H),
5.00 (d, J = 15.84 Hz, 1 H), 4.83 (s, 1 H), 3.76–3.69 (m, 4 H), 3.63–
3.54 (m, 1 H), 2.10 (d, J = 7.51 Hz, 3 H), 1.83–1.78 (m, 1 H), 1.66–
1.58 (m, 3 H), 1.33–1.25 (m, 3 H), 1.04–1.00 (m, 3 H).
13C NMR (75 MHz, CDCl3): δ = 168.0, 165.2, 159.0, 136.9, 129.6
(2), 128.6, 128.0, 127.5, 126.7, 124.3, 121.8, 116.7, 114.0, 105.6,
59.7, 55.2, 51.0, 49.0, 48.6, 32.7, 32.4, 25.3, 24.5 (2), 14.9.
HRMS: m/z calcd for C31H35N3O3: 497.2678; found: 497.2657.
HRMS: m/z calcd for C31H35N3O3: 497.2678; found: 497.2678.
Au(PPh3)OTf-Catalyzed Cyclization of 5a–d to 6a–d; General
Procedure
PtCl2-Catalyzed Cyclization of 5a–d to 7a–d; General Proce-
dure
To a glass vial were loaded Au(PPh3)Cl (5 mol%) and AgOTf (5
mol%) along with CHCl3 (2 mL). The respective Ugi product 5a–d
(0.25 mmol) was added and the reaction mixture was stirred at
50 °C in a screw capped vial until completion (3 h). After comple-
tion, the mixture was partitioned between EtOAc (100 mL) and H2O
(50 mL). The organic layer was washed with brine (50 mL), dried
(MgSO4) and evaporated under reduced pressure. The residue ob-
tained was purified by silica gel column chromatography (10%
Et2O in CH2Cl2) to afford compound 6a–d (Table 1).
To a glass vial was loaded PtCl2 (5 mol%) along with CHCl3 (2
mL). The respective Ugi product 5a–d (0.25 mmol) was added and
the reaction mixture was stirred at 50 °C in a screw capped vial until
completion (14 h). After completion, the mixture was partitioned
between EtOAc (100 mL) and H2O (50 mL). The organic layer was
washed with brine (50 mL), dried (MgSO4) and evaporated under
reduced pressure. The residue obtained was purified by silica gel
column chromatography (20% Et2O in CH2Cl2) to afford compound
7a–d (Table 1).
(E)-6-Benzyl-N-tert-butyl-4-ethylidene-1-methyl-5-oxo-4,5,6,7-
tetrahydro-1H-pyrrolo[2,3-c]pyridine-7-carboxamide (6a)
Yield: 57 mg (62%); yellow solid; mp 190–192 °C.
1H NMR (300 MHz, CDCl3): δ = 7.32–7.26 (m, 5 H), 6.95 (q, J =
7.59 Hz, 1 H), 6.63 (d, J = 2.85 Hz, 1 H), 6.39 (d, J = 2.85 Hz, 1 H),
5.60 (d, J = 14.79 Hz, 1 H), 5.34 (br s, 1 H), 4.84 (s, 1 H), 3.99 (d,
J = 14.75 Hz, 1 H), 3.57 (s, 3 H), 2.10 (d, J = 7.55 Hz, 1 H), 1.21 (s,
9 H).
7-Benzyl-N-tert-butyl-1,4-dimethyl-6-oxo-1,6,7,8-tetrahydro-
pyrrolo[2,3-c]azepine-8-carboxamide (7a)
Yield: 72 mg (79%), white solid; mp 142–144 °C.
1H NMR (300 MHz, CDCl3): δ = 7.28–7.21 (m, 5 H), 6.48 (d,
J = 2.85 Hz, 1 H), 6.17 (d, J = 2.85 Hz, 1 H), 5.96 (s, 1 H), 5.37–
5.32 (m, 2 H), 4.74 (s 1 H), 4.48 (d, J = 14.98 Hz, 1 H), 3.04 (s, 3
H), 2.14 (s, 3 H), 1.15 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 167.4, 167.2, 141.4, 137.3, 128.9,
128.6, 127.9, 127.8, 123.1, 121.4, 118.8, 105.9, 55.9, 52.6, 51.6,
33.1, 28.3, 22.8.
13C NMR (75 MHz, CDCl3): δ = 167.9, 164.8, 136.3, 129.4, 128.7,
128.5, 127.6, 124.6, 123.8, 121.8, 116.1, 105.3, 61.6, 51.6, 49.3,
34.2, 28.4, 14.8.
HRMS: m/z calcd for C22H27N3O2: 365.2103; found: 365.2107.
HRMS: m/z calcd for C22H27N3O2: 365.2103; found: 365.2119.
N-tert-Butyl-1,4-dimethyl-6-oxo-7-pentyl-1,6,7,8-tetrahydro-
pyrrolo[2,3-c]azepine-8-carboxamide (7b)
Yield: 71 mg (82%), white solid; mp 147–149 °C.
(E)-N-tert-Butyl-4-ethylidene-1-methyl-5-oxo-6-pentyl-4,5,6,7-
tetrahydro-1H-pyrrolo[2,3-c]pyridine-7-carboxamide (6b)
Yield: 66 mg (76%); green solid; mp 119–121 °C.
1H NMR (300 MHz, CDCl3): δ = 6.61 (d, J = 2.87 Hz, 1 H), 6.19 (d,
J = 2.87 Hz, 1 H), 5.87 (s, 1 H), 5.63 (br s, 1 H), 4.81 (s, 1 H), 3.90–
3.80 (m, 1 H), 3.71 (s, 3 H), 3.46–3.36 (m, 1 H), 2.11 (s, 3 H), 1.62–
1.55 (m, 2 H), 1.29–1.24 (m, 13 H), 0.85 (t, J = 7.08 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 167.3, 167.2, 141.0, 128.1, 123.2,
121.4, 118.8, 106.0, 58.0, 51.8, 50.6, 33.9, 28.9, 28.6, 28.4, 22.8,
22.4, 13.9.
1H NMR (300 MHz, CDCl3): δ = 6.86 (q, J = 7.50 Hz, 1 H), 6.66 (d,
J = 2.78 Hz, 1 H), 6.38 (d, J = 2.89 Hz, 1 H), 5.34 (br s, 1 H), 4.94
(s, 1 H), 4.09–4.02 (m, 1 H), 3.69 (s, 3 H), 2.99–2.89 (m, 1 H), 2.07
(d, J = 7.67 Hz, 3 H), 1.63–1.58 (m, 2 H), 1.32–1.31 (m, 4 H), 1.23
(s, 9 H), 0.88 (t, J = 6.6 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 168.4, 164.5, 128.6, 124.6, 124.0,
121.9, 116.1, 105.3, 62.7, 51.6, 47.4, 34.4, 29.1, 28.4, 26.8, 22.4,
14.8, 13.9.
HRMS: m/z calcd for C20H31N3O2: 345.2416; found: 345.2391.
HRMS: m/z calcd for C20H31N3O2: 345.2416; found: 345.2419.
1-Benzyl-N-cyclohexyl-7-(4-methoxybenzyl)-4-methyl-6-oxo-
1,6,7,8-tetrahydropyrrolo[2,3-c]azepine-8-carboxamide (7d)
Yield: 75 mg (60%); off-white solid; mp 204–206 °C.
(E)-6-[2-(1H-Indol-3-yl)ethyl]-N-(tert-butyl)-4-ethylidene-1-
methyl-5-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-7-
carboxamide (6c)
1H NMR (300 MHz, CDCl3): δ = 7.37–7.29 (m, 3 H), 7.08 (d,
J = 8.57 Hz, 2 H), 7.02 (d, J = 7.59 Hz, 2 H), 6.84 (d, J = 8.57 Hz,
2 H), 6.70 (d, J = 2.89 Hz, 1 H), 6.26 (d, J = 2.89 Hz, 1 H), 5.92 (s,
1 H), 4.93–4.85 (m, 2 H), 4.71 (s, 1 H), 4.65 (d, J = 14.45 Hz, 1 H),
4.41 (d, J = 15.61 Hz, 1 H), 4.04 (d, J = 14.45 Hz, 1 H), 3.78 (s, 3
H), 3.45–3.39 (m, 1 H), 2.12 (s, 3 H), 1.49–1.46 (m, 5 H), 1.19–1.15
(m, 2 H), 1.02 (m, 1 H), 0.69–0.59 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 167.4, 166.7, 159.5, 140.9, 137.4,
130.3, 129.6, 129.3, 128.3, 127.5, 126.5, 123.1, 122.5, 119.4, 114.4,
106.2, 55.3, 51.7, 50.6, 48.3, 32.4, 32.2, 25.3, 24.5, 22.9.
Yield: 63 mg (60%); green solid; mp 181–183 °C.
1H NMR (300 MHz, CDCl3): δ = 8.04 (br s, 1 H), 7.68 (d, J = 8.08
Hz, 1 H), 7.33 (d, J = 8.24 Hz, 1 H), 7.16 (t, J = 7.45 Hz, 1 H), 7.08–
7.01 (m, 2 H), 6.91 (q, J = 7.56 Hz, 1 H), 6.60 (d, J = 2.84 Hz, 1 H),
6.37 (d, J = 2.84 Hz, 1 H), 5.36 (br s, 1 H), 4.73 (s, 1 H), 4.44–4.36
(m, 1 H), 3.44 (s, 3 H), 3.25–3.08 (m, 3 H), 2.10 (d, J = 7.50 Hz, 3
H), 1.19 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 168.3, 164.9, 136.2, 128.4, 127.3,
124.4, 124.3, 122.2, 122.1, 122.0, 119.4, 119.0, 116.0, 113.0, 110.9,
105.2, 62.9, 51.6, 48.6, 34.1, 28.4, 23.3, 14.8.
Synthesis 2013, 45, 2571–2582
© Georg Thieme Verlag Stuttgart · New York

PAPER
Gold(I)- and Platinum(II)-Catalyzed Alkyne Activation
2579
HRMS: m/z calcd for C31H35N3O3: 497.2678; found: 497.2671.
N-[2-(tert-Butylamino)-1-(1H-indol-2-yl)-2-oxoethyl]-N-(4-
methoxybenzyl)-3-phenylpropiolamide (14c)
Yield: 869 mg (88%); orange solid; mp 135–137 °C; rotameric ratio
~1:5.
1H NMR (300 MHz, CDCl3): δ = 9.72 (br s, 1 H), 7.55–7.47 (m, 3
H), 7.41–7.33 (m, 4 H), 7.22–7.18 (m, 3 H), 7.09 (t, J = 7.33 Hz, 1
H), 6.80–6.69 (m, 2 H), 6.29 (s, 0.84 H), 5.79 (s, 0.80 H), 5.62–5.60
(m, 0.36 H), 5.33 (s, 0.80 H), 5.29 (s, 0.22 H), 5.05 (d, J = 15.86 Hz,
0.16 H), 4.95 (d, J = 15.82 Hz, 0.82 H), 4.78 (d, J = 15.86 Hz, 0.82
H), 4.64 (d, J = 15.86 Hz, 0.19 H), 3.76–3.74 (m, 3 H), 1.30 (s, 1.50
H), 1.25 (s, 7.50 H).
N-[2-(Cyclohexylamino)-2-oxo-1-(thiophen-2-yl)ethyl]-N-(4-
methoxybenzyl)but-2-ynamide (9a)
The Ugi adduct 9a was synthesized following the same procedure
used for the Ugi adducts 5a–d; yield: 730 mg (86%); white solid;
mp 140–142 °C; rotameric ratio ~1:5.
1H NMR (300 MHz, CDCl3): δ = 7.34 (d, J = 5.25 Hz, 0.18 H), 7.25
(d, J = 5.25 Hz, 0.82 H), 7.10 (d, J = 8.66 Hz, 2 H), 7.04–6.99 (m,
1.20 H), 6.90–6.87 (m, 0.80 H), 6.77 (d, J = 8.66 Hz, 2 H), 6.21 (s,
0.17 H), 5.93 (d, J = 8.05 Hz, 0.76 H), 5.79 (s, 0.79 H), 5.47 (d,
J = 8.27 Hz, 0.16 H), 4.82–4.71 (m, 1.60 H), 4.64 (d, J = 15.06 Hz,
0.20 H), 4.33 (d, J = 15.06 Hz, 0.20 H), 3.77 (s, 3 H), 3.67–3.63 (m,
1 H), 2.01 (s, 0.52 H), 1.96 (s, 2.47 H), 1.88–1.83 (m, 0.93 H), 1.73–
1.51 (m, 5.10 H), 1.32–1.23 (m, 2 H), 1.14–0.98 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 166.9, 166.7, 159.0, 158.9, 155.5
(2), 136.6, 136.0, 129.9, 129.7, 129.4, 128.8, 128.7, 128.4, 127.5,
127.3, 126.6, 126.3, 113.9, 113.6, 91.8, 90.6, 73.5, 73.2, 61.9, 57.5,
55.2 (2), 51.2, 48.6, 48.5, 46.5, 32.5, 32.4, 32.3, 25.4 (2), 24.6 (2),
24.5, 4.2, 4.1.
13C NMR (75 MHz, CDCl3): δ = 166.4, 159.2, 156.2, 136.4, 132.6,
132.5, 132.4, 131.8, 131.0, 130.3, 129.1, 128.5, 128.4 (3), 127.8,
127.2, 122.6, 120.5, 119.9, 119.8, 114.0, 113.9, 113.6, 111.6, 105.0,
92.0, 81.5, 57.9, 55.2, 53.1, 51.7, 28.5 (2).
HRMS: m/z calcd for C31H31N3O3: 493.2365; found: 493.2372.
N-[2-(tert-Butylamino)-1-(1H-indol-2-yl)-2-oxoethyl]-N-(4-
methoxybenzyl)-3-(4-methoxyphenyl)propiolamide (14d)
Yield: 723 mg (69%); off-white solid; mp 96–98 °C.
1H NMR (300 MHz, CDCl3): δ = 9.77 (br s, 1 H), 7.53 (d, J = 8.15
Hz, 1 H), 7.42–7.34 (m, 3 H), 7.20–7.18 (m, 3 H), 7.08 (t, J = 7.46
Hz, 1 H), 6.84–6.76 (m, 4 H), 6.30 (s, 1 H), 5.84 (br s, 1 H), 5.39 (s,
1 H), 4.94 (d, J = 15.80 Hz, 1 H), 4.77 (d, J = 15.80 Hz, 1 H), 3.80
(s, 3 H), 3.74 (s, 3 H), 1.24 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 166.5, 161.3, 159.2, 156.5, 136.4,
134.5, 134.4 132.0, 130.4, 129.1, 128.0, 127.2, 122.5, 120.5, 119.8,
114.3, 114.2 (2), 113.9, 111.8, 111.6, 104.9, 92.8, 81.0, 57.7, 55.3
(2), 55.2, 53.0, 51.6, 28.5.
HRMS: m/z calcd for C24H28N2O3S: 424.1821; found: 424.1835.
N-Cyclohexyl-7-(4-methoxybenzyl)-4-methyl-6-oxo-7,8-di-
hydro-6H-thieno[2,3-c]azepine-8-carboxamide (11a)
The product 11a was synthesized following the same procedure
used for cyclized products 7a–d; yield: 62 mg (58%); off-white sol-
id; mp 208–210 °C.
1H NMR (300 MHz, CDCl3): δ = 7.28 (m, 3 H), 7.09 (d, J = 5.27
Hz, 1 H), 6.86 (d, J = 8.66 Hz, 2 H), 6.14 (s, 1 H), 5.16 (d, J = 8.50
Hz, 1 H), 5.18–5.15 (m, 2 H), 4.63 (d, J = 14.61 Hz, 1 H), 3.80 (s, 3
H), 3.58 (m, 1 H), 2.17 (s, 3 H), 1.70–1.64 (m, 5 H), 1.25 (m, 2 H),
1.07 (m, 1 H), 0.88 (m, 1 H), 0.74 (m, 1 H).
HRMS: m/z calcd for C32H33N3O4: 523.2471; found: 523.2464.
N-[2-(Cyclohexylamino)-1-(1H-indol-2-yl)-2-oxoethyl]-N-cy-
clopropylpent-2-ynamide (14e)
Yield: 603 mg (77%); off-white solid; mp 205–207 °C.
13C NMR (75 MHz, CDCl3): δ = 166.8, 166.1, 159.5, 139.4, 138.2,
135.4, 130.2, 128.8, 126.4, 124.8, 124.1, 114.3, 57.9, 55.3, 51.6,
48.6, 32.7, 32.5, 25.3, 24.5, 23.4.
1H NMR (300 MHz, CDCl3): δ = 9.80 (br s, 1 H), 7.59 (d, J = 8.05
Hz, 1 H), 7.36 (d, J = 8.05 Hz, 1 H), 7.23–7.09 (m, 2 H), 6.51 (s, 1
H), 5.58 (d, J = 8.04 Hz, 1 H), 5.26 (s, 1 H), 3.80–3.70 (m, 1 H),
3.05–2.98 (m, 1 H), 2.40 (q, J = 7.46 Hz, 2 H), 1.90–1.75 (m, 2 H),
1.61–1.51 (m, 2 H), 1.36–1.18 (m, 6 H), 1.07–0.81 (m, 7 H).
13C NMR (75 MHz, CDCl3): δ = 166.6, 158.8, 136.5, 133.1, 127.2,
122.7, 120.5, 119.9, 111.7, 104.4, 97.2, 74.4, 62.5, 48.9, 33.5, 32.8,
32.5, 25.3, 24.7 (2), 12.8, 10.7, 8.0.
HRMS: m/z calcd for C24H28N2O3S: 424.1821; found: 424.1824.
Ugi Products 14a–g and 15a,b
The Ugi adducts 14a–g and 15a,b were synthesized following the
same procedure used for Ugi adducts 5a–d (Table 2).
N-[2-(tert-Butylamino)-1-(1H-indol-2-yl)-2-oxoethyl]-N-(4-
methoxybenzyl)but-2-ynamide (14a)
Yield: 647 mg (75%); off-white solid; mp 166–168 °C.
HRMS: m/z calcd for C24H29N3O2: 391.2260; found: 391.2266.
1H NMR (300 MHz, CDCl3): δ = 9.69 (br s, 1 H), 7.52 (d, J = 8.26
Hz, 1 H), 7.34 (d, J = 8.26 Hz, 1 H), 7.21–7.08 (m, 4 H), 6.78 (d,
J = 8.44 Hz, 2 H), 6.24 (s, 1 H), 5.76 (br s, 1 H), 5.25 (s, 1 H), 4.86
(d, J = 15.77 Hz, 1 H), 4.67 (d, J = 15.77 Hz, 1 H), 3.76 (s, 3 H),
2.00 (s, 3 H), 1.22 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 166.4, 159.2, 156.2, 136.4, 132.0,
129.1, 127.8, 127.2, 122.5, 120.5, 119.8, 113.9, 111.6, 104.9, 91.2,
73.3, 57.7, 55.2, 53.1, 51.6, 28.5, 4.1.
N-Butyl-N-[2-(tert-butylamino)-1-(1H-indol-2-yl)-2-oxoethyl]-
3-phenylpropiolamide (14f)
Yield: 455 mg (53%); brown solid; mp 150–152 °C.
1H NMR (300 MHz, CDCl3): δ = 9.98 (br s, 1 H), 7.60 (d, J = 7.89
Hz, 1 H), 7.53–7.51 (m, 2 H), 7.42–7.34 (m, 4 H), 7.22 (t, J = 7.40
Hz, 1 H), 7.12 (t, J = 7.34 Hz, 1 H), 6.53 (s, 1 H), 6.06 (br s, 1 H),
5.55 (s, 1 H), 3.81–3.71 (m, 1 H), 3.59–3.49 (m, 1 H), 1.71–1.50 (m,
4 H), 1.32 (s, 9 H), 0.84 (t, J = 7.38 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 167.1, 155.9, 136.4, 132.4, 132.1,
130.3, 128.6, 127.3, 122.6, 120.6, 120.2, 120.0, 111.7, 104.7, 91.4,
81.4, 57.7, 51.8, 49.8, 31.2, 28.5, 19.9, 13.6.
HRMS: m/z calcd for C26H29N3O3: 431.2209; found: 431.2207.
N-[2-(Cyclohexylamino)-1-(1H-indol-2-yl)-2-oxoethyl]-N-(4-
methoxybenzyl)but-2-ynamide (14b)
Yield: 439 mg (48%); off-white solid; mp 165–167 °C.
1H NMR (300 MHz, CDCl3): δ = 9.67 (br s, 1 H), 7.53 (d, J = 7.46
Hz, 1 H), 7.34 (d, J = 7.46 Hz, 1 H), 7.20–7.09 (m, 4 H), 6.80 (d,
J = 7.46 Hz, 2 H), 6.27 (s, 1 H), 5.67 (br s, 1 H), 5.18 (s, 1 H), 4.79
(s, 2 H), 3.76–3.65 (m, 4 H), 1.99 (s, 3 H), 1.88–1.51 (m, 5 H), 1.31–
1.19 (m, 2 H), 1.08–0.90 (m, 3 H).
HRMS: m/z calcd for C27H31N3O2: 429.2416; found: 429.2425.
N-[2-(tert-Butylamino)-1-(1-methyl-1H-indol-2-yl)-2-oxoethyl]-
N-(4-methoxybenzyl)but-2-ynamide (14g)
Yield: 676 mg (76%); white solid; mp 186–188 °C; rotameric ratio
~1:1.2.
1H NMR (300 MHz, CDCl3): δ = 7.94 (s, 0.43 H), 7.85 (s, 0.55 H),
7.59 (d, J = 7.84 Hz, 0.45 H), 7.52 (d, J = 7.84 Hz, 0.56 H), 7.15–
6.99 (m, 3 H), 6.52–6.50 (m, 1.54 H), 6.44 (s, 0.59 H), 6.31–6.25
(m, 3 H), 6.17 (s, 1 H), 5.01 (d, J = 15.97 Hz, 0.55 H), 4.90 (d,
J = 15.00 Hz, 0.44 H), 4.48 (d, J = 15.97 Hz, 0.52 H), 4.03 (d,
13C NMR (75 MHz, CDCl3): δ = 166.2, 159.3, 156.3, 136.5, 131.9,
129.2, 127.6, 127.1, 122.6, 120.5, 119.9, 113.9, 111.6, 105.0, 91.1,
73.2, 57.6, 55.3, 55.2, 53.3, 48.7, 32.7, 32.4, 25.4, 24.7, 24.6, 4.1.
HRMS: m/z calcd for C28H31N3O3: 457.2365; found: 457.2376.
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J = 15.00 Hz, 0.45 H), 3.54–3.51 (m, 3 H), 3.08–3.05 (m, 3 H),
2.08–2.02 (m, 3 H), 1.31–1.27 (m, 9 H).
13C NMR (75 MHz, CDCl3): δ = 167.8, 166.7, 159.3, 142.8, 135.9,
134.8, 129.9, 129.0, 125.4, 122.6, 120.8, 120.1, 119.0, 114.3, 112.8,
111.9, 55.2, 48.9, 32.6, 32.3, 29.6, 25.2, 24.6, 24.5, 24.0.
13C NMR (75 MHz, CDCl3): δ = 136.7, 167.4, 157.7, 154.7, 136.9,
136.7, 134.1, 134.0, 129.7, 129.2, 129.1, 128.1, 127.4, 126.6, 126.4,
121.7, 121.4, 120.4, 120.1, 119.3, 119.0, 112.5 (2), 109.4, 109.2,
102.7, 102.6, 91.1, 90.4, 74.0, 72.9, 57.4, 54.8, 54.7, 52.7, 50.4 (2),
49.5, 46.2, 28.8, 28.2, 3.6, 3.3.
HRMS: m/z calcd for C28H31N3O3: 457.2365; found: 457.2366.
N-tert-Butyl-2-(4-methoxybenzyl)-3-oxo-5-phenyl-1,2,3,10-tet-
rahydroazepino[3,4-b]indole-1-carboxamide (16c)
Yield: 109 mg (88%); white solid; mp 286–288 °C.
1H NMR (300 MHz, CDCl3): δ = 9.11 (br s, 1 H), 7.49–7.39 (m, 5
H), 7.19–7.10 (m, 3 H), 7.02 (t, J = 7.76 Hz, 1 H), 6.85 (t, J = 7.45
Hz, 1 H), 6.75 (d, J = 7.85 Hz, 2 H), 6.56 (d, J = 8.05 Hz, 1 H), 6.34
(s, 1 H), 5.69 (br s, 1 H), 5.09 (s, 1 H), 4.83 (br s, 2 H), 3.73 (s, 3 H),
1.10 (s, 9 H).
HRMS: m/z calcd for C27H31N3O3: 445.2365; found: 445.2364.
N-[1-(Benzo[b]thiophen-2-yl)-2-(tert-butylamino)-2-oxoethyl]-
N-(4-methoxybenzyl)but-2-ynamide (15a)
Yield: 586 mg (70%); white solid; mp 126–128 °C; rotameric ratio
~1:3.
1H NMR (300 MHz, CDCl3): δ = 7.81–7.64 (m, 2 H), 7.36–7.29 (m,
2 H), 7.23–7.11 (m, 3 H), 6.78–6.69 (m, 2 H), 6.10 (s, 0.19 H), 6.00
(br s, 0.73 H), 5.74 (s, 0.78 H), 5.48 (br s, 0.17 H), 4.82 (s, 1.52 H),
4.66–4.48 (m, 0.39 H), 3.75 (s, 0.65 H), 3.71 (s, 2.36 H), 1.99 (s, 3
H), 1.25 (s, 7 H), 1.14 (s, 2 H).
13C NMR (75 MHz, CDCl3): δ = 166.5, 159.3, 144.3, 139.8, 135.8,
135.7, 129.9, 128.9, 128.5, 128.4, 125.6, 122.7, 120.6, 120.3, 114.2,
111.6, 111.5, 58.8, 55.3, 52.6, 52.0, 28.2.
HRMS: m/z calcd for C31H31N3O3: 493.2365; found: 493.2354.
13C NMR (75 MHz, CDCl3): δ = 166.5, 159.0, 155.6, 140.7, 138.7,
137.4, 130.1, 128.9, 128.7, 126.1, 124.6, 124.2, 123.6, 122.1, 114.2,
113.7, 90.9, 73.5, 58.9, 55.2, 51.7, 28.4, 28.1, 4.1.
N-tert-Butyl-2-(4-methoxybenzyl)-5-(4-methoxyphenyl)-3-oxo-
1,2,3,10-tetrahydroazepino[3,4-b]indole-1-carboxamide (16d)
Yield: 111 mg (85%); off-white solid; mp 299–302 °C.
1H NMR (400 MHz, DMSO-d6): δ = 11.50 (br s, 1 H), 7.46 (d,
J = 8.40 Hz, 1 H), 7.31 (d, J = 8.40 Hz, 2 H), 7.20 (d, J = 8.05 Hz,
2 H), 7.08 (t, J = 7.56 Hz, 1 H), 6.98 (d, J = 8.66 Hz, 2 H), 6.85–
6.82 (m, 3 H), 6.48 (d, J = 8.02 Hz, 1 H), 6.11 (br s, 1 H), 5.64 (s, 1
H), 5.31 (s, 1 H), 4.72 (d, J = 14.99 Hz, 1 H), 4.62 (d, J = 14.74 Hz,
1 H), 3.80 (m, 3 H), 3.69 (3 H), 1.10 (s, 9 H).
HRMS: m/z calcd for C26H28N2O3S: 448.1821; found: 448.1806.
N-[1-(Benzo[b]thiophen-2-yl)-2-(tert-butylamino)-2-oxoethyl]-
N-(4-methoxybenzyl)-3-phenylpropiolamide (15b)
Yield: 970 mg (95%); yellow solid; mp 66–68 °C; rotameric ratio
~1:3.
1H NMR (300 MHz, CDCl3): δ = 7.77–7.66 (m, 2 H), 7.5–7.52 (m,
0.44 H), 7.47–7.44 (m, 1.54 H), 7.40–7.28 (m, 6.62 H), 7.18 (d,
J = 8.74 Hz, 1.60 H), 6.80 (d, J = 8.75 Hz, 0.50 H), 6.71 (d, J = 8.75
Hz, 1.51 H), 6.07 (s, 0.23 H), 6.01 (br s, 0.68 H), 5.83 (s, 0.74 H),
5.52 (br s, 0.15 H), 4.93 (s, 1.42 H), 4.77–4.59 (m, 0.46 H), 3.76 (s,
0.76 H), 3.70 (s, 2.28 H), 1.28 (s, 7.25 H), 1.12 (s, 1.72 H).
13C NMR (75 MHz, CDCl3): δ = 166.5, 166.4, 159.4, 159.0, 155.7,
140.7, 138.7, 137.4, 132.8, 132.5, 130.5, 130.3 (2), 129.5, 128.9,
128.7, 128.5, 126.3, 124.9, 124.7, 124.4, 124.3, 123.8, 123.7, 120.1,
114.3, 113.8, 92.9, 91.7, 81.8, 81.5, 63.1, 58.9, 55.3, 55.2, 51.8,
51.7, 28.5, 28.2.
13C NMR (100 MHz, DMSO-d6): δ = 166.8, 165.8, 159.7, 158.5,
141.6, 137.1, 135.7, 132.0, 129.5, 129.3, 125.4, 121.5, 119.7, 119.5,
113.8, 113.7, 112.3, 109.7, 66.9, 55.1, 55.0, 50.8, 27.9, 25.0.
HRMS: m/z calcd for C32H33N3O4: 523.2471; found: 523.2460.
N-Cyclohexyl-2-cyclopropyl-5-ethyl-3-oxo-1,2,3,10-tetrahy-
droazepino[3,4-b]indole-1-carboxamide (16e)
Yield: 90 mg (92%); yellow solid; mp 136–138 °C.
1H NMR (400 MHz, DMSO-d6): δ = 11.78 (br s, 1 H), 7.69 (d,
J = 7.88 Hz, 1 H), 7.47 (d, J = 7.88 Hz, 1 H), 7.17 (t, J = 7.69 Hz, 1
H), 7.09 (t, J = 7.36 Hz, 1 H), 6.93 (d, J = 8.15 Hz, 1 H), 5.68 (s, 1
H), 5.16 (s, 1 H), 3.55 (m, 1 H), 2.94–2.87 (m, 2 H), 2.63–2.53 (m,
1 H), 1.60–1.47 (m, 4 H), 1.24–1.12 (m, 5 H), 1.03 (t, J = 7.41 Hz,
3 H), 0.85–0.67 (m, 3 H), 0.61–0.54 (m, 1 H), 0.43–0.38 (m, 1 H).
HRMS: m/z calcd for C31H30N2O3S: 510.1977; found: 510.1984.
Compounds 16a–g and 17a,b
13C NMR (100 MHz, DMSO-d6): δ = 169.0, 166.6, 146.1, 136.8,
136.1, 125.3, 122.2, 120.8, 120.3, 119.2, 112.8, 110.5, 60.0, 55.2,
49.1, 33.3, 32.4, 32.3, 29.7, 25.4, 25.3, 13.4, 9.8, 6.4.
The products 16a–f and 17a,b were synthesized following the same
procedure used for the cyclized products 6a–d (Table 2).
N-(tert-Butyl)-2-(4-methoxybenzyl)-5-methyl-3-oxo-1,2,3,10-
tetrahydroazepino[3,4-b]indole-1-carboxamide (16a)
Yield: 87 mg (77%); off-white solid; mp 95–97 °C.
1H NMR (300 MHz, CDCl3): δ = 9.11 (br s, 1 H), 7.75 (t, J = 3.51
Hz, 1 H), 7.20–7.11 (m, 5 H), 6.77 (d, J = 7.92 Hz, 2 H), 6.05 (s, 1
H), 5.71 (br s, 1 H), 4.98 (d, J = 14.52 Hz, 1 H), 4.92 (s, 1 H), 4.49
(d, J = 13.56 Hz, 1 H), 3.75 (s, 3 H), 2.48 (s, 3 H), 1.11 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 166.6, 159.3, 142.8, 135.8, 135.1,
129.9, 129.1, 125.4, 122.6, 120.8, 120.2, 119.1, 114.2, 112.9, 111.8,
55.3, 51.8, 28.2, 23.9, 14.1.
HRMS: m/z calcd for C24H29N3O2: 391.2260; found: 391.2267.
N-tert-Butyl-2-butyl-3-oxo-5-phenyl-1,2,3,10-tetrahydroazepi-
no[3,4-b]indole-1-carboxamide (16f)
Yield: 85 mg (79%); yellow solid; mp 264–267 °C.
1H NMR (300 MHz, DMSO-d6): δ = 11.69 (br s, 1 H), 7.50 (d,
J = 8.27 Hz, 1 H), 7.44–7.38 (m, 5 H), 7.09 (t, J = 7.66 Hz, 1 H),
6.82 (t, J = 7.48 Hz, 1 H), 6.49–6.40 (m, 2 H), 5.96 (s, 1 H), 5.27 (s,
1 H), 3.83 (m, 1 H), 3.27 (m, 1 H), 1.48–11.45 (m, 2 H), 1.09 (m, 11
H), 0.79 (t, J = 7.34 Hz, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 166.5, 166.0, 141.1, 139.8,
137.3, 135.8, 128.6, 128.3, 128.0, 125.3, 121.6, 121.3, 119.6, 119.4,
112.3, 109.6, 58.3, 54.8, 51.0, 29.6, 28.0, 19.3, 13.6.
HRMS: m/z calcd for C26H29N3O3: 431.2209; found: 431.2224.
N-Cyclohexyl-2-(4-methoxybenzyl)-5-methyl-3-oxo-1,2,3,10-
tetrahydroazepino[3,4-b]indole-1-carboxamide (16b)
HRMS: m/z calcd for C27H31N3O2: 429.2416; found: 429.2403.
Yield: 103 mg (90%); off-white solid; mp 226–228 °C.
1H NMR (300 MHz, CDCl3): δ = 9.58 (br s, 1 H), 7.73 (d, J = 7.75
Hz, 1 H), 7.25–7.02 (m, 5 H), 6.74 (d, J = 7.66 Hz, 2 H), 6.02 (s, 1
H), 5.70 (br s, 1 H), 5.04 (s, 1 H), 4.90 (d, J = 14.34 Hz, 1 H), 4.50
(d, J = 14.34 Hz, 1 H), 3.73 (s, 3 H), 3.59 (m, 1 H), 2.48 (s, 3 H),
1.58 (m, 3 H), 1.25 (m, 4 H), 1.06 (m, 1 H), 0.86 (m, 2 H).
N-(tert-Butyl)-2-(4-methoxybenzyl)-5,10-dimethyl-3-oxo-
1,2,3,10-tetrahydroazepino[3,4-b]indole-1-carboxamide (16g)
Yield: 92 mg (83%); white solid; mp 237–239 °C.
1H NMR (300 MHz, CDCl3): δ = 7.77 (d, J = 7.93 Hz, 1 H), 7.46 (d,
J = 8.10 Hz, 1 H), 7.20 (t, J = 7.17 Hz, 1 H), 7.13–7.10 (m, 3 H),
6.76 (d, J = 8.32 Hz, 2 H), 6.11 (s, 1 H), 5.84 (s, 1 H), 5.41 (s, 1 H),
Synthesis 2013, 45, 2571–2582
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Gold(I)- and Platinum(II)-Catalyzed Alkyne Activation
2581
5.08 (d, J = 14.33 Hz, 1 H), 4.35 (d, J = 14.33 Hz, 1 H), 3.67 (s, 3
H), 3.38 (s, 3 H), 2.35 (s, 3 H), 1.12 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 167.2, 167.1, 159.4, 140.5, 138.5,
137.8, 130.8, 130.3, 125.2, 122.7, 121.2, 121.0, 120.9, 114.7, 112.2,
111.6, 57.0, 55.9, 52.0, 51.9, 30.2, 29.0, 24.1.
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Williams, D. E.; Tahir, A.; van Soest, R.; Andersen, R. J.
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HRMS: m/z calcd for C27H31N3O3: 445.2365; found: 445.2361.
N-(tert-Butyl)-2-(4-methoxybenzyl)-5-methyl-3-oxo-2,3-di-
hydro-1H-benzo[4,5]thieno[2,3-c]azepine-1-carboxamide (17a)
Yield: 90 mg (80%); white solid; mp 235–237 °C.
1H NMR (300 MHz, CDCl3): δ = 7.93 (d, J = 8.02 Hz, 1 H), 7.79 (d,
J = 8.21 Hz, 1 H), 7.41–7.36 (m, 2 H), 7.28 (d, J = 8.47 Hz, 2 H),
6.86 (d, J = 8.49 Hz, 2 H), 6.26 (s, 1 H), 5.27 (br s, 1 H), 4.91 (d,
J = 14.53 Hz, 1 H), 4.83 (s, 1 H), 4.49 (d, J = 14.45 Hz, 1 H), 3.80
(m, 3 H), 2.42 (3 H), 1.13 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 166.6, 165.9, 159.6, 140.0, 139.1,
138.0, 137.3, 132.5, 130.3, 128.7, 125.9, 124.9, 124.8, 123.6, 122.8,
114.5, 59.2, 55.3, 51.8, 51.4, 28.2, 23.0.
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HRMS: m/z calcd for C26H28N2O3S: 448.1821; found: 448.1829.
N-(tert-Butyl)-2-(4-methoxybenzyl)-3-oxo-5-phenyl-2,3-di-
hydro-1H-benzo[4,5]thieno[2,3-c]azepine-1-carboxamide (17b)
Yield: 116 mg (91%); white solid; mp 248–250 °C.
1H NMR (300 MHz, CDCl3): δ = 7.74 (d, J = 8.17 Hz, 1 H), 7.36–
7.23 (m, 8 H), 7.06 (t, J = 7.55 Hz, 1 H), 6.88 (d, J = 8.59 Hz, 2 H),
6.74 (d, J = 8.35 Hz, 1 H), 6.51 (s, 1 H), 5.39 (s, 1 H), 4.96–4.90 (m,
2 H), 4.62 (d, J = 14.50 Hz, 1 H), 3.80 (s, 3 H), 1.10 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 166.9, 165.7, 159.6, 142.7, 139.5,
139.1, 139.0, 137.5, 131.0, 130.4, 129.0, 128.5 (2), 128.1, 126.0,
124.7, 124.4, 124.3, 122.4, 114.5, 59.3, 55.3, 51.9, 51.8, 28.1.
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HRMS: m/z calcd for C31H30N2O3S: 510.1977; found: 510.1976.
Acknowledgment
Support was provided by the research fund of the KU Leuven and
the FWO [Fund for Scientific Research – Flanders (Belgium)]. A.K.
is thankful to EMA2 experts (Erasmus Mundus Action 2, Lot 11
Asia: Experts) for providing a doctoral exchange scholarship and
D.D.V. is thankful to EMECW, lot 13 (Erasmus Mundus External
Cooperation Window, Lot-13) for providing a doctoral scholarship.
The authors thank Ir. B. Demarsin for HRMS measurements.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
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