Sequential combination of ruthenium-, base-, and gold-catalysis - A new approach to the synthesis of medicinally important heterocycles

Article abstract of DOI:10.1002/ejoc.201100040

A general approach to the high-yielding synthesis of medicinally important heterocycles was achieved through the sequential combination of ring-closing metathesis, base-induced ring opening (BIRO), hydroamination, and a Diels-Alder reaction of functionalized allyl-(2-allylphenyl)amines in the presence of a catalytic amount of Grubbs' second-generation catalyst, base (tBuOK), and [AuCl(PPh₃)]/AgOTf. Herein, we also demonstrate the important electronic factors in the BIRO of N-substituted-benzo[b]azepines for the regioselective synthesis of functionalized (Z)-N-substituted-2-(buta-1,3-dienyl) phenylamines in very good yields with high purity; these are very good, useful compounds in medicinal chemistry. We also discovered the selective cascade synthesis of privileged hexahydrophenanthridines from (Z)-N-substituted-2-(buta- 1,3-dienyl)phenylamines by gold catalysis in moderate to good yields with >99 % diastereomeric excess. The possible reaction mechanism for the unusual hydroamination followed by [4+2] cycloaddition of functionalized (Z)-N-substituted-2-(buta-1,3-dienyl)phenylamines through gold catalysis is discussed in this work. A novel process for the synthesis of highly substituted, medicinally important heterocycles was achieved through the sequential combination of ring-closing methathesis, base-induced ring opening, hydroamination, and Diels-Alder reaction of functionalized allyl-(2-allylphenyl) amines in the presence of a catalytic amount of [Ru], base, and [Au] (see scheme). Copyright

Full text of DOI:10.1002/ejoc.201100040

FULL PAPER
DOI: 10.1002/ejoc.201100040
Sequential Combination of Ruthenium-, Base-, and Gold-Catalysis –
A New Approach to the Synthesis of Medicinally Important Heterocycles
Dhevalapally B. Ramachary*[a] and Vidadala V. Narayana[a]
Keywords: Base-induced ring opening / Heterocycles / Homogeneous catalysis / Hydroamination / Ring-closing metathesis
A general approach to the high-yielding synthesis of medici-
nally important heterocycles was achieved through the se-
quential combination of ring-closing metathesis, base-in-
duced ring opening (BIRO), hydroamination, and a Diels–
Alder reaction of functionalized allyl-(2-allylphenyl)amines
in the presence of a catalytic amount of Grubbs’ second-
generation catalyst, base (tBuOK), and [AuCl(PPh3)]/AgOTf.
Herein, we also demonstrate the important electronic factors
in the BIRO of N-substituted-benzo[b]azepines for the re-
gioselective synthesis of functionalized (Z)-N-substituted-2-
(buta-1,3-dienyl)phenylamines in very good yields with high
purity; these are very good, useful compounds in medicinal
chemistry. We also discovered the selective cascade synthesis
of privileged hexahydrophenanthridines from (Z)-N-substi-
tuted-2-(buta-1,3-dienyl)phenylamines by gold catalysis in
moderate to good yields with Ͼ99% diastereomeric excess.
The possible reaction mechanism for the unusual hydro-
amination followed by [4+2] cycloaddition of functionalized
(Z)-N-substituted-2-(buta-1,3-dienyl)phenylamines through
gold catalysis is discussed in this work.
Introduction
Benzannulated nitrogen heterocycles are well-known bio-
logically active compounds that display a wide range of
pharmacological activities.[1] In particular, N-substituted-
2,3-dihydro-1H-benzo[b]azepines,
N-substituted-2-(buta-
1,3-dienyl)phenylamines, N-substituted-1,2,3,4-tetrahydro-
quinolines, and functionalized hexahydrophenanthridines
display promising biological activities.[1] Thus, the diversity-
oriented synthesis of these heterocycles represents an im-
portant task because of the widespread occurrence of such
structural scaffolds and their use as building blocks in phar-
maceuticals. For example, OPC-31260 (A), OPC-41061 (B),
an inhibitor of N-type calcium channels (C), Strobilurin I
(D), a molecule with antiparasitic activity (E), and lycorine
(F) are some of the compounds that are very useful in me-
dicinal chemistry (Figure 1).[1]
We have designed a novel methodology for the synthesis
of highly functionalized N-substituted-benzo[b]azepines, N-
substituted-2-(buta-1,3-dienyl)phenylamines, N-substituted-
2-methyl-2H-quinolines, and N-substituted-phenanthrid-
ines starting from simple dienes (Scheme 1). A ruthenium-
catalyzed ring-closing metathesis (RCM), base-induced ring
opening (BIRO), and gold-catalyzed hydroamination of ole-
fins followed by [4+2] cycloaddition reactions are the cru-
cial steps in the designed reaction sequence. Interestingly,
to the best of our knowledge, there have not been any re-
Figure 1. Examples of important heterocycles in medicinal chemis-
try.
[a] School of Chemistry, University of Hyderabad,
Hyderabad 500046, India
Fax: +91-40-23012460
Scheme 1. A sequential RCM, BIRO, and gold-catalyzed hydro-
amination of olefins followed by [4+2] cycloaddition in one pot. Pg
= protecting group, Fg = functional group.
E-mail: ramsc@uohyd.ernet.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100040.
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Eur. J. Org. Chem. 2011, 3514–3522

Medicinally Important Heterocycles
ports of the synthesis of three different heterocycles from Table 1. Reaction optimization for the sequential RCM/BIRO or
RCM/I reaction of 1aa–1ef in one pot.
one common precursor. Herein, we report, for the first time,
a sequential one-pot approach to the synthesis of highly
functionalized benzo[b]azepines (2), (Z)-2-(buta-1,3-dienyl)-
phenylamines (3), 2-methyl-2H-quinolines (4), and phen-
anthridines (5) starting from simple dienes (1) by sequential
RCM/BIRO and gold-catalyzed hydroamination followed
by [4+2] cycloaddition reactions.[2]
Results and Discussion
The investigation into the newly designed sequential one-
pot reactions was initiated by synthesizing a library of sub-
stituted heterodienes/heteroenynes 1 as precursors in very
Entry
X
Pg
Time [h]
Product
Yield [%][a]
good yields through a combination of N-allylation, N-pro-
pargylation, C-allylation, and N-protection on anilines as
key steps (see Schemes S1–S4 in the Supporting Infor-
mation). First, the scope of the sequential RCM/BIRO one-
pot reactions was investigated with a variety of N-substi-
tuted heterodienes 1aa–1ef by comparing the electronic fac-
tors, as shown in Table 1. Reaction of ethyl allyl-(2-allyl-4-
chlorophenyl)carbamate (1aa) with Grubbs’ first-generation
catalyst G (3 mol-%) in CH2Cl2 at 25 °C for 15 h gave the
benzo[b]azepine 6aa in Ͼ95% conversion, which on further
treatment with tBuOK (3 equiv.) in DMSO at 0–25 °C for
0.5 h gave the interesting ethyl (2-buta-1,3-dienyl-4-chlo-
rophenyl)carbamate (cis-3aa) with moderate yield (75%)
and Ͼ99% Z selectivity under one-pot conditions (Table 1,
entry 1). In a similar manner, the sequential RCM/BIRO
1[b]
2[c]
3
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Me
CO2Et (a)
CO2Et (a)
CO2Et (a)
Ts[d] (b)
15 + 0.5
3 + 0.5
5 + 0.5
3 + 0.5
4 + 0.5
3aa
3aa
3aa
3ab
3ac
3ad
3ae
2af
2ef
75
85
92
88
80
71
40
55
75
4
5
6
7
COPh (c)
COCH3 (d) 4 + 0.5
COCF3 (e) 3 + 1.0
H (f)
H (f)
8[e,f]
9[f,g]
24 + 3.0
27 + 1.0
[a] Yield refers to the product purified by column chromatography.
[b] RCM reaction performed with Grubbs first-generation catalyst
G (3 mol-%). [c] The RCM reactions were performed with Hov-
eyda–Grubbs first-generation catalyst I (3 mol-%). [d] Ts = tosyl.
[e] p-Toluenesulfonic acid (pTSA) (1 equiv.) was used as a co-cata-
lyst for the RCM reaction. [f] The BIRO reaction was performed
on the isolated RCM product. [g] The RCM reactions were per-
formed with Hoveyda–Grubbs first-generation catalyst I (5 mol-%)
one-pot reaction of 1aa using Hoveyda–Grubbs’ first-gen- and trifluoroacetic acid (TFA; 2 equiv.) were used as co-catalysts.
eration catalyst I (3 mol-%) in CH2Cl2 at 25 °C for 3 h fol-
lowed by treatment with tBuOK (3 equiv.) in DMSO at 0–
25 °C for 0.5 h gave the carbamate cis-3aa in 85% yield with
Ͼ99% Z selectivity (Table 1, entry 2). Interestingly, the se- (6ef) in 50% yield, which on further treatment with tBuOK
quential RCM/BIRO one-pot reaction of 1aa using Grubbs’ (3 equiv.) in DMSO at 0–25 °C for 1 h gave only isomerized
second-generation catalyst H (3 mol-%) in CH2Cl2 at 25 °C 7-methyl-2,3-dihydro-1H-benzo[b]azepine (2ef) in 75%
for only 5 h followed by treatment with tBuOK (3 equiv.) yield instead of (Z)-3ef, as shown in Table 1, entry 9. From
in DMSO at 0–25 °C for 0.5 h gave the carbamate cis-3aa these results, sequential RCM/BIRO one-pot reactions
in very good yield (92%) with Ͼ99% Z selectivity (Table 1, proved to be extremely facile with heterodienes 1aa–1ef,
entry 3).[3]
containing electron-withdrawing groups on nitrogen, as
After obtaining this preliminary information, we further shown in Table 1. We envisioned the optimized conditions
investigated the sequential RCM/BIRO one-pot reactions to be the reaction of 1aa with catalyst H (3 mol-%) in
on heterodienes containing different N-protecting groups to CH2Cl2 at 25 °C for 5 h to give the benzo[b]azepine 6aa in
study the electronic factors. Interestingly, sequential RCM/ Ͼ99% conversion, which on in situ treatment with tBuOK
BIRO one-pot reactions on heterodienes containing N-Ts (3 equiv.) in DMSO at 0–25 °C for 0.5 h gave the one-pot
1ab, N-COPh 1ac, N-COCH3 1ad, and N-COCF3 1ae gave product cis-3aa in 92% yield and Ͼ99% Z selectivity
the expected products (Z)-3ab–3ae in very good yields with (Table 1, entry 3). The structure and regiochemistry of (Z)-
high Z selectivity, as shown in Table 1, entries 4–7. But the 2-(buta-1,3-dienyl)phenylamines
3 were confirmed by
RCM reaction of the heterodiene 1af (containing N-H/Ar- NMR spectroscopic analysis and also finally confirmed by
Cl) with catalyst H/pTSA gave the 7-chloro-2,5-dihydro- X-ray structure analysis of cis-3ac, as shown in Figure S1
1H-benzo[b]azepine (6af) in 75% yield, which on further in the Supporting Information.[4]
treatment with tBuOK (3 equiv.) in DMSO at 0–25 °C for
With the optimized reaction conditions in hand, the
3 h gave only isomerized 7-chloro-2,3-dihydro-1H-benzo- scope of the ruthenium and base-induced RCM/BIRO and
[b]azepine 2af in 55% yield instead of (Z)-3af, as shown in RCM/isomerization one-pot reactions was investigated with
Table 1, entry 8. In a similar manner, the RCM reaction of a variety of heterodienes and heteroenynes 1, as shown in
the heterodiene 1ef (containing N-H/Ar-Me) with catalyst Table 2. The sequential RCM reaction of the substituted
I/TFA gave the 7-methyl-2,5-dihydro-1H-benzo[b]azepine heterodienes 1ba–1ib (containing N-CO2Et, N-COCF3, or
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D. B. Ramachary, V. V. Narayana
FULL PAPER
N-Ts) with Grubbs’ second-generation catalyst H (3 mol-%)
We have also utilized base-induced double-bond isomer-
in CH2Cl2 at 25 °C for 3–8 h gave the functionalized ization with N-alkylation reactions in one pot to deliver the
benzo[b]azepines 6ba–6ib in Ͼ99% conversion, which on in functionalized 2,3-dihydro-1H-benzo[b]azepines 2 in good
situ treatment with tBuOK (3 equiv.) in DMSO at 0–25 °C yields (Scheme 2). Reaction of 2,5-dihydro-1H-benzo[b]-
for 0.5–1.0 h gave the functionalized (Z)-2-(buta-1,3-dienyl)- azepine (6bf) with tBuOK (3 equiv.) at 0–25 °C for 1 h, fol-
phenylamines 3ba–3ib in very good yields with high Z selec- lowed by in situ treatment with allyl bromide (a) or propar-
tivity, as shown in Table 2, entries 1–11 (read the entry gyl bromide (b) at 25 °C for 3–18 h gave the one-pot prod-
numbers from left to right sequentially). Interestingly, enyne ucts N-allyl-2,3-dihydro-1H-benzo[b]azepine (2bfa) and 1-
metathesis of the substituted heteroenynes 1jb and 1kb [N- prop-2-ynyl-2,3-dihydro-1H-benzo[b]azepine (2bfb) in 65
Ts] with Grubbs’ first-generation catalyst G (8 mol-%) in and 40% yield, respectively; these were good starting mate-
CH2Cl2 at 25 °C for 24 h gave the benzo[b]azepines 6jb–6kb rials for the synthesis of drug analogues of A–C (Figure 1).
in Ͼ99% conversion, which on in situ treatment with base
gave the products cis-3jb–3kb in moderate yields (Table 2,
entries 12 and 13). To support the role of electronic factors
in BIRO reactions, we performed these sequential reactions
on benzo[b]azepines 6bf, 6bg, and 6fh (containing N-H, N-
Ph, and N-PMP; PMP = para-methoxyphenyl), as shown
in Table 2, entries 14–16. Interestingly, in situ treatment of
benzo[b]azepines 6bf, 6bg, and 6fh with tBuOK (3 equiv.)
in DMSO at 0–25 °C for 1.0 h gave only the double-bond-
isomerized RCM/isomerization products 2bf, 2bg, and 2fh
in 75, 82, and 65% yields, respectively (Table 2, entries 14–
16).
Scheme 2. Reaction conditions: (a) tBuOK (3 equiv.), DMSO
(0.05 m), 25 °C, 1h; H2C=CHCH2Br (a, 2 equiv.), 25 °C, 3 h, 65%;
(b) tBuOK (3 equiv.), DMSO (0.05 m), 25 °C, 1 h; HCϵCCH2Br
(b, 2 equiv.), 25 °C, 18 h, 40%.
Table 2. Chemically diverse libraries of functionalized amines 2/3.[a]
After understanding the sequential one-pot combination
of RCM, BIRO, isomerization, and alkylation reactions, we
were also interested in investigating the intra- and intermo-
lecular hydroamination of (Z)-aminodienes 3, as shown in
Tables 3 and 4. The hydroamination of olefins is a promi-
nent and atom-economic reaction for the synthesis of N-
heterocycles.[5] In particular, intra- and intermolecular hy-
droamination displays an efficient route for accessing multi-
functional N-heterocycles for natural-product synthesis and
pharmaceuticals.[5] Since the seminal discovery of metallo-
cene-catalyzed hydroamination by Marks and co-workers,[6]
hydroamination emerged as an important reaction to study
many aspects of N-heterocycles. Starting from simple ami-
noalkenes, the scope of metal-promoted hydroamination re-
actions was quickly extended to various unsaturated mole-
cules, including aminoalkynes, aminoallenes, conjugated
(E)-aminodienes and aminodialkenes, aminodialkynes, and
aminoalkenalkynes.[5] However, the metal-catalyzed intra-
or intermolecular hydroamination of conjugated (Z)-amino-
dienes 3 was not known and the resulting products 4 and 5
could have a wide range of uses in pharmaceutical chemis-
try (see Scheme 1).[5]
After thorough investigation of intra- and intermolecular
hydroamination of conjugated (Z)-aminodienes 3aa–3ad
with gold chlorides and/or silver salts, we found that
[AuCl(PPh3)]/AgOTf (5 mol-%) in toluene at reflux were
suitable conditions for the designed hydroaminations, as
[a] Yield refers to the product purified by column chromatography.
shown in Table 3 and Table S1 in the Supporting Infor-
[b] RCM reactions were performed with Grubbs first-generation
mation.[7] Interestingly, the reaction of N-Ts-(Z)-aminodi-
catalyst G (8 mol-%). [c] pTSA (1 equiv.) was used as a co-catalyst
ene 3ab with [AuCl(PPh3)]/AgOTf (5 mol-%) in the toluene
at 100 °C for 24 h selectively gave 4ab in 50% yield without
in the RCM reaction. [d] The BIRO reaction was performed on the
isolated RCM product.
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Medicinally Important Heterocycles
5ab (Table 3, entry 1). In a similar manner, treatment of N- Table 4. Synthesis of N-substituted phenanthridines 5.[a]
Ts-(Z)-aminodienes 3eb–3gb with [AuCl(PPh3)]/AgOTf
(5 mol-%) in toluene at 100 °C for 6–7 h only gave intramo-
lecular hydroamination products 4eb–4gb in moderate
yields (Table 3, entries 2–4). However, the reaction of N-
CO2Et-(Z)-aminodiene 3aa with [AuCl(PPh3)]/AgOTf
(5 mol-%) in toluene at 100 °C for 24 h gave the unexpected
cascade intermolecular hydroamination/[4+2] cycloaddition
Entry
X
Time
[h]
Product 4
Product 5
product 5aa in 55% yield with Ͼ99% diastereomeric excess
(de) and also 4aa in 20% yield (Table 3, entry 5).[8] In a
similar manner, the reaction of N-COCH3-(Z)-aminodiene
3ad with [AuCl(PPh3)]/AgOTf (5 mol-%) in toluene at
100 °C for 24 h only gave cascade product 5ad in 40% yield
with Ͼ99% de (Table 3, entry 6). Herein, products 4 were
generated through gold-catalyzed intramolecular hydroa-
mination of 3, and cascade product 5aa was formed
through gold-catalyzed intermolecular hydroamination of
3aa followed by unusual gold-catalyzed intramolecular
[4+2] cycloaddition reactions. The product selectivity of
these reactions was mainly controlled by electronic factors,
as shown by the nature of the N-protecting groups.[8]
(Yield [%][a]
)
(Yield [%][a]
)
1
2
3
4
Cl
H
Br
CH3
OCH3
CO2Et
Cl
24
10
24
24
6
8
24
4aa (20)
4ba (25)
4da (24)
4ea (26)
4fa (30)
4ga (20)
–
5aa (55)
5ba (40)
5da (47)
5ea (43)
5fa (25)
5ga (60)
5ad (40)
5
6
7[b]
[a] Yield refers to the column purified product. [b] E = COCH3.
Even though further studies are required to firmly eluci-
date the mechanism of these sequential cascade reactions
through [AuCl(PPh3)]/AgOTf catalysis, a possible reaction
mechanism for intra- and intermolecular hydroamination
followed by selective [4+2] cycloaddition is illustrated in
Scheme 3. Treatment of (Z)-diene 3 with in situ generated
active gold catalyst [Au(PPh3)]OTf forms the reactive com-
plex 7, which can undergo both intra- or intermolecular
hydroamination based on the electronic nature of the amine
group. In the first route, intramolecular hydroamination of
7 followed by reductive elimination of unstable intermediate
8 generates the expected product 4 with free catalyst [Au]
for further cycles, as shown in Scheme 3. In the second
route, intermolecular hydroamination of 7 with 3 followed
by reductive elimination of unstable intermediate 10 gener-
ates the key intermediate 11 with free catalyst [Au], as
shown in Scheme 3. Activation of the (Z)-diene from key
intermediate 11 with [Au(PPh3)]OTf gives the intramolecu-
Table 3. Synthesis of functionalized 2-methyl-1,2-dihydroquinolines
4.
Entry
X
Pg
Time [h]
Product
Yield [%][a]
1
2
3
4
5
6
Cl
Ts
Ts
Ts
Ts
24
6
6
7
24
4ab
50
30
25
25
20, 55
40
CH3
OCH3
CO2Et
Cl
4eb
4fb
4gb
4aa, 5aa
5ad
CO2Et
COCH3 24
Cl
[a] Yield refers to the column-purified product.
To explore the unusual gold-catalyzed intra- and inter-
molecular hydroamination followed by selective [4+2] cyclo-
addition reactions, we chose a variety of (Z)-ethyl-2-buta-
1,3-dienyl-carbamates, 3aa–3ga, and N-(2-buta-1,3-dienyl-
4-chlorophenyl)acetamide (3ad) as substrates (Table 4).
Compounds 3aa–3ga were transformed into functionalized,
N-substituted 2-methyl-2H-quinolines 4aa–4ga in moderate
yields and highly functionalized N-substituted phenanthri-
dines 5aa–5ga in good yields with Ͼ99% de through a com-
bination of gold/silver catalysis, as shown in Table 4, entries
1–6. Cascade products 5aa–5ga were formed in good yields
and with high diastereoselectivity through gold catalysis
without showing much effect from substitution (X) on the
benzene rings of 3aa–3ga. The structure and stereochemis-
try of N-substituted phenanthridines 5 were confirmed by
NMR spectroscopic analysis and also finally confirmed by
X-ray structure analysis of 5aa (Figure S2 in the Supporting
Information).[4]
Scheme 3. Proposed reaction mechanism.
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D. B. Ramachary, V. V. Narayana
FULL PAPER
Method B – N-Monoallylations: The starting anilines (1 mmol) were
monoallylated by treatment with allyl bromide (1.1 mmol) and
K2CO3 (1.2 mmol) in dry DMF (2 mL, 0.5 m) at 0–25 °C for 24 h.
The crude reaction mixture was worked up with an aqueous solu-
tion of NH4Cl and the aqueous layer was extracted with dichloro-
methane (2ϫ20 mL). The combined organic layers were dried
(Na2SO4), filtered, and concentrated. Pure N-monoallylated prod-
ucts were obtained by column chromatography (silica gel, mixture
of hexane/ethyl acetate).
lar [4+2] cycloaddition product 5 with high selectivity
(Ͼ99% de) through stepwise or concerted pathways, as
shown in compound 12.
Conclusions
We have shown the strength of a sequential, multicata-
lytic, one-pot approach in the diversity-oriented synthesis
of highly functionalized N-substituted benzo[b]azepines
2/6, N-substituted 2-(buta-1,3-dienyl)phenylamines 3, N-
substituted 2-methyl-2H-quinolines 4, and N-substituted
phenanthridines 5 from simple substrates by RCM/BIRO,
RCM/isomerization, isomerization/alkylation, intramolecu-
lar hydroamination, and cascade intermolecular hydroa-
mination/[4+2] cycloaddition reactions.
Method C – N-Propargylation: The enynes 1j and 1k were prepared
by treating the corresponding C-allylated anilines (1.0 mmol) with
propargyl bromide (130.8 mg, 1.1 mmol) and K2CO3 (165.8 mg,
1.2 mmol) in DMF (2 mL, 0.5 m) at room temperature for 24 h.
The crude reaction mixture was worked up with an aqueous solu-
tion of NH4Cl and the aqueous layer was extracted with dichloro-
methane (2ϫ20 mL). The combined organic layers were dried
(Na2SO4), filtered, and concentrated. Pure products 1j and 1k were
obtained by column chromatography (silica gel, mixture of hexane/
ethyl acetate).
Experimental Section
Procedure B – C-Allylation Through Claisen Rearrangement: The
corresponding N-allylated products (1 mmol), BF3·Et2O (1 mmol),
and freshly distilled xylene (1 mL, 1.0 m) were added to a sealed
glass tube and the mixture was heated at 135–140 °C under N2 for
2 to 8 h. Upon cooling the reaction mixture to room temperature,
the mixture was diluted with dichloromethane (10 mL), and
washed with an aqueous solution of NH4Cl (2 mL) and brine
(2 mL). The separated organic layer was dried (Na2SO4), filtered,
and concentrated under reduced pressure. Pure products 1 were
obtained by column chromatography (basic alumina, mixture of
hexane/ethyl acetate).
1
General Methods: The H and 13C NMR spectra were recorded at
400 and 100 MHz, respectively. The chemical shifts are reported in
ppm relative to TMS (δ = 0 ppm) for H NMR spectroscopy and
1
relative to the central CDCl3 resonance (δ = 77.0 ppm) for 13C
NMR spectroscopy. In the 13C NMR spectra, the nature of the
carbon atoms (C, CH, CH2 or CH3) was determined by recording
the DEPT-135 experiment, and is given in parentheses. The cou-
pling constants, J, are given in Hz. Column chromatography was
performed by using Acme silica gel (particle size 0.063–0.200 mm).
High-resolution mass spectra were recorded on micromass ESI-
TOF mass spectrometer. GC–MS was performed on a GC–MS-
QP2010 mass spectrometer. IR spectra were recorded on an FT/IR-
5300 instrument. Elemental analyses were recorded on a Thermo
Finnigan Flash EA 1112 analyzer. Mass spectra were recorded on
either a VG7070H mass spectrometer using the EI technique or on
an LCMS-2010 A mass spectrometer. The X-ray diffraction mea-
surements were carried out at 298 K on an automated Enraf-Noni-
ous MACH 3 diffractometer using graphite monochromated,
MoKα (λ = 0.71073 Å) radiation with CAD4 software or the X-ray
intensity data were measured at 298 K on a SMART APEX CCD
area detector system equipped with a graphite monochromator and
a MoKα fine-focus sealed tube (λ = 0.71073 Å). For TLC, silica
gel plates 60 F254 were used and compounds were visualized by
irradiation with UV light and/or by treatment with a solution of
p-anisaldehyde (23 mL), concentrated H2SO4 (35 mL), acetic acid
(10 mL), and ethanol (900 mL) followed by heating.
Allyl-(2-allyl-4-bromophenyl)amine (1d): Prepared following the
procedure B and purified by column chromatography using EtOAc/
hexane and isolated as a liquid. IR (neat): ν
= 3412 (N–H),
˜
max
1575, 1502, 1260, 918, 665 cm–1. H NMR (CDCl3): δ = 7.21 (dd,
J = 8.4, 2.0 Hz, 1 H), 7.14 (d, J = 2.4 Hz, 1 H), 6.47 (d, J = 8.4 Hz,
1 H), 5.96–5.84 (m, 2 H, olefinic-H), 5.23 (dd, J = 16.8, 1.6 Hz, 1
H, olefinic-H), 5.17–5.07 (m, 3 H, olefinic-H), 3.82 (s, 1 H, N-H),
3.74 (d, J = 5.2 Hz, 2 H, NCH2), 3.24 (d, J = 6.4 Hz, 2 H, ArCH2)
ppm. 13C NMR (CDCl3, DEPT-135): δ = 145.0 (C), 135.0 (CH),
134.8 (CH), 132.2 (CH), 130.1 (CH), 125.6 (C), 116.9 (CH2), 116.2
(CH2), 112.2 (CH), 108.9 (C), 46.2 (CH2), 36.0 (CH2) ppm. MS:
m/z = 251.90 [M + H+].
1
(2-Allyl-4-chlorophenyl)prop-2-ynylamine (1k): Prepared by follow-
ing procedures A and B and purified by column chromatography
using EtOAc/hexane and isolated as a liquid. IR (neat): ν
=
˜
max
3295 (CϵC–H), 1606, 1503, 1436, 1260, 1000, 666 cm–1. 1H NMR
(CDCl3): δ = 7.19 (d, J = 8.0 Hz, 1 H), 7.09 (s, 1 H, Ar-H), 6.69
(d, J = 7.6 Hz, 1 H), 5.99–5.90 (m, 1 H, olefinic-H), 5.21 (d, J =
10.0 Hz, 1 H, olefinic-H), 5.14 (d, J = 17.2 Hz, 1 H, olefinic-H),
3.96 (s, 3 H, NCH2CϵC-H, N-H), 3.29 (d, J = 4.8 Hz, 2 H), 2.26
(s, 1 H, NCH2CϵC-H) ppm. 13C NMR (CDCl3, DEPT-135): δ =
143.6 (C), 134.9 (CH), 129.7 (CH), 127.3 (CH), 126.2 (C), 123.1
(C), 117.1 (CH2), 112.4 (CH), 80.6 (C, NCH2CϵC-H), 71.5 (CH,
NCH2CϵC-H), 35.9 (CH2, NCH2CϵC-H), 33.6 (CH2) ppm. MS:
m/z = 206.05 [M + H+].
Experimental Procedures for the Synthesis of Highly Functionalized
N-Substituted 2-(Buta-1,3-dienyl)phenylamines: The synthesis of
functionalized N-substituted 2-(buta-1,3-dienyl)phenylamines (3)
from the corresponding anilines involves the following four or five-
step sequence:
Procedure A – N-Alkylations
Method A – N-Diallylations: The starting anilines (1 mmol) were
diallylated by treatment with allyl bromide (3 mmol) and sodium
hydride (4 mmol) in dry DMF (2 mL, 0.5 m) at 0–25 °C for 2–8 h.
The crude reaction mixture was worked up with an aqueous solu-
tion of NH4Cl and the aqueous layer was extracted with dichloro-
methane (2ϫ20 mL). The combined organic layers were dried
(Na2SO4), filtered, and concentrated. Pure N-diallylated products
were obtained by column chromatography (silica gel, mixture of
hexane/ethyl acetate).
Procedure C – N-Protection
Method A – Synthesis of 1aa–1ga, 1ab, 1eb–1kb, and 1ac: The corre-
sponding amines 1a–k (1 mmol) were protected by treatment with
pyridine (6 mmol) and Pg-Cl [Pg = CO2Et (a), Ts (b), or COPh (c);
2 mmol] in dry CH2Cl2 (10 mL, 0.1 m) at 0–25 °C for 24 h. The
reaction mixture was quenched with water and extracted with
3518
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3514–3522

Medicinally Important Heterocycles
CH2Cl2 (3ϫ20 mL). The combined organic layers were washed
with dilute HCl (2 mL) and brine, dried with (Na2SO4), filtered,
and concentrated. Pure products were obtained by column
chromatography (silica gel, mixture of hexane/ethyl acetate).
Procedure D – RCM/BIRO Reactions in One Pot
Method A: A 10 mL oven-dried round-bottomed flask equipped
with a stirring bar was charged with diene 1aa–1ib (0.5 mmol) and
Grubbs’ second-generation catalyst H (12.73 mg, 0.015 mmol,
3 mol-%) in dry CH2Cl2 (10 mL, 0.05 m) and the reaction mixture
was stirred under N2 at room temperature for 2–5 h. CH2Cl2 was
distilled off at ambient pressure and the crude reaction mixture
was dissolved in dry DMSO (10 mL, 0.05 m) before potassium tert-
butoxide (168.3 mg, 1.5 mmol, 3 equiv.) was added at 0 °C. The
reaction mixture was stirred at 25 °C for 1 h. The crude reaction
mixture was worked up with water and the aqueous layer was ex-
tracted with diethyl ether (2ϫ20 mL). The combined organic layers
were dried (Na2SO4), filtered, and concentrated. Pure products
3aa–3ib were obtained by column chromatography (silica gel, mix-
ture of hexane/ethyl acetate).
Ethyl Allyl-(2-allyl-4-chlorophenyl)carbamate (1aa): Prepared by
following the procedure C, method A, and purified by column
chromatography using EtOAc/hexane and isolated as a liquid. IR
(neat): ν
= 1708 (N–C=O), 1644, 1485, 1408, 1297, 1027, 771,
˜
max
1
648 cm–1. H NMR (CDCl3): δ = 7.24 (d, J = 2.0 Hz, 1 H), 7.17
(dd, J = 8.4, 2.0 Hz, 1 H), 7.01 (d, J = 8.4 Hz, 1 H), 5.94–5.84 (m,
2 H, olefinic-H), 5.14–5.05 (m, 4 H, olefinic-H), 4.37–4.29 (m, 1
H, NCH2), 4.20–4.05 (m, 2 H, OCH2CH3), 3.86 (dd, J = 13.2,
5.6 Hz, 1 H, NCH2), 3.25 (d, J = 5.6 Hz, 2 H, ArCH2), 1.31–1.12
(m, 3 H, OCH2CH3) ppm. 13C NMR (CDCl3, DEPT-135): δ =
155.3 (C, N-C=O), 139.8 (C), 138.4 (C), 135.4 (CH), 133.2 (CH),
132.9 (C), 130.0 (CH), 129.9 (CH), 127.0 (CH), 118.4 (CH2), 117.1
(CH2), 61.6 (CH2, OCH2CH3), 53.2 (CH2), 35.1 (CH2), 14.5 (CH3,
OCH2CH3) ppm. MS: m/z = 280.00 [M + H+].
Ethyl (2-Buta-1,3-dienyl-4-chlorophenyl)carbamate (3aa): Prepared
by following procedure D, method A, and purified by column
chromatography using EtOAc/hexane and isolated as a solid. IR
Method B – Synthesis of 1ad: Acetic anhydride (1 mL) was added
to the diallyl derivative 1a (51.75 mg, 0.25 mmol) and the reaction
mixture was stirred at 25 °C for 15 h. The reaction mixture was
quenched with water and extracted with CH2Cl2. The separated
organic layer was dried (Na2SO4), filtered, and concentrated under
reduced pressure. Pure product 1ad was obtained by column
chromatography (silica gel, mixture of hexane/ethyl acetate).
(neat): ν
= 3277 (N–H), 1689 (N–C=O), 1529, 1249, 1065, 659
˜
max
cm–1. H NMR (CDCl3): δ = 7.96 (d, J = 7.2 Hz, 1 H), 7.24 (dd,
J = 8.8, 2.4 Hz, 1 H), 7.14 (d, J = 2.0 Hz, 1 H), 6.54 (br. s, 1 H,
N-H), 6.48–6.38 (m, 2 H, olefinic-H), 6.26 (d, J = 9.2 Hz, 1 H,
olefinic-H), 5.46–5.38 (m, 1 H, olefinic-H), 5.27 (d, J = 8.4 Hz, 1
H, olefinic-H), 4.20 (q, J = 7.2 Hz, 2 H, OCH2CH3), 1.29 (t, J =
7.2 Hz, 3 H, OCH2CH3) ppm. 13C NMR (CDCl3, DEPT-135): δ =
153.4 (C, N-C=O), 135.0 (CH), 134.2 (2ϫ C), 132.2 (CH), 129.4
(CH), 128.2 (CH), 128.0 (C), 124.1 (CH), 121.7 (CH2), 120.9 (CH),
61.4 (CH2, OCH2CH3), 14.5 (CH3, OCH2CH3) ppm. MS: m/z =
252.00 [M + H+]. C13H14ClNO2 (251.07): calcd. C 62.03, H 5.61,
N 5.56; found C 62.12, H 5.55, N 5.61.
1
N-Allyl-N-(2-allyl-4-chlorophenyl)acetamide (1ad): Prepared by fol-
lowing procedure C, method B, and purified by column chromatog-
raphy using EtOAc/hexane and isolated as a liquid. IR (neat): ν
˜
max
= 1659 (N–C=O), 1483, 1385, 1097, 654 cm–1. H NMR (CDCl3):
δ = 7.32 (s, 1 H, Ar-H), 7.23 (dd, J = 8.4, 2.4 Hz, 1 H), 7.01 (d, J
= 8.4 Hz, 1 H), 5.89–5.82 (m, 2 H, olefinic-H), 5.18–5.10 (m, 3 H,
olefinic-H), 5.04 (d, J = 16.8 Hz, 1 H, olefinic-H), 4.68 (dd, J =
14.4, 5.6 Hz, 1 H, NCH2), 3.69 (dd, J = 14.0, 7.2 Hz, 1 H, NCH2),
3.29 (d, J = 6.4 Hz, 2 H, ArCH2), 1.76 (s, 3 H, COCH3) ppm. 13C
NMR (CDCl3, DEPT-135): δ = 170.2 (C, N-C=O), 139.6 (C), 139.5
(C), 134.8 (CH), 134.2 (C), 132.5 (CH), 130.8 (CH), 130.7 (CH),
127.6 (CH), 118.7 (CH2), 117.8 (CH2), 51.6 (CH2), 34.9 (CH2), 22.4
(CH3) ppm. MS: m/z = 248.10 [M – H+ ].
1
Method B: A 10 mL oven-dried round-bottomed flask equipped
with a stirring bar was charged with enyne 1jb–1kb (0.5 mmol) and
Grubbs’ first-generation catalyst G (32.9 mg, 0.04 mmol, 8 mol-%)
in dry CH2Cl2 (25 mL, 0.02 m) and the reaction mixture was stirred
under N2 at room temperature for 24 h. CH2Cl2 was distilled off
at ambient pressure and the crude reaction mixture was dissolved
in dry DMSO (10 mL, 0.05 m) before potassium tert-butoxide
(168.3 mg, 1.5 mmol, 3 equiv.) was added at 0 °C. The reaction
mixture was stirred at 25 °C for 1 h. The crude reaction mixture
was worked up with water and the aqueous layer was extracted
with diethyl ether (2ϫ20 mL). The combined organic layers were
dried (Na2SO4), filtered, and concentrated. Pure products 3jb–3kb
were obtained by column chromatography (silica gel, mixture of
hexane/ethyl acetate).
Method C – Synthesis of 1ae: Trifluoroacetic anhydride (420 mg,
2 mmol) was added to a solution of 1a (207 mg, 1 mmol), Et3N
(101.2 mg, 1 mmol), and 4-dimethylaminopyridine (DMAP;
122.2 mg, 1 mmol) in dry CH2Cl2 (5 mL), and the reaction mixture
was stirred at 25 °C for 24 h. The reaction mixture was quenched
with water and extracted with CH2Cl2 (3ϫ20 mL). The combined
organic layers were washed with dilute HCl (2 mL) and brine, dried
with (Na2SO4), filtered, and concentrated. Pure product 1ae was
obtained by column chromatography (silica gel, mixture of hexane/
ethyl acetate).
4-Methyl-N-[2-(3-methylene-penta-1,4-dienyl)phenyl]benzenesulfon-
amide (3jb): Prepared by following procedure D, method B, and
purified by column chromatography using EtOAc/hexane and iso-
lated as a liquid. IR (neat): ν
= 3263 (N–H), 1490, 1332, 1161,
˜
max
N-Allyl-N-(2-allyl-4-chlorophenyl)-2,2,2-trifluoroacetamide (1ae): 1091, 820, 736 cm–1. H NMR (CDCl3): δ = 7.61 (d, J = 7.6 Hz, 2
1
Prepared by following procedure C, method C, and purified by
column chromatography using EtOAc/hexane and isolated as a li-
H), 7.46 (d, J = 8.4 Hz, 1 H), 7.22–7.18 (m, 3 H, Ph-H), 7.08 (d, J
= 7.2 Hz, 1 H), 7.03 (d, J = 7.2 Hz, 1 H), 6.59 (s, 1 H, N-H), 6.31–
6.24 (m, 2 H, olefinic-H), 6.13 (d, J = 12.0 Hz, 1 H, olefinic-H),
quid. IR (neat): ν
= 1702 (N–C=O), 1487, 1415, 1211, 925, 680
˜
max
cm–1. 1H NMR (CDCl3): δ = 7.33 (s, 1 H, Ar-H), 7.22 (dd, J = 5.29 (d, J = 17.6 Hz, 1 H, olefinic-H), 5.12 (d, J = 10.8 Hz, 1 H,
8.4, 2.0 Hz, 1 H), 7.03 (d, J = 8.4 Hz, 1 H), 5.90–5.79 (m, 2 H,
olefinic-H), 5.24–5.10 (m, 4 H, olefinic-H), 4.76 (dd, J = 14.4,
olefinic-H), 5.01 (s, 1 H, olefinic-H), 4.72 (s, 1 H, olefinic-H), 2.38
(s, 3 H, Ar-CH3) ppm. 13C NMR (CDCl3, DEPT-135): δ = 143.8
6.0 Hz, 1 H, NCH2), 3.66 (dd, J = 16.8, 8.0 Hz, 1 H, NCH2), 3.29 (C), 141.7 (C), 137.5 (CH), 136.6 (C), 133.4 (C), 131.6 (CH), 130.1
(t, J = 6.0 Hz, 2 H, ArCH2) ppm. 13C NMR (CDCl3, DEPT-135): (C), 129.6 (CH), 129.5 (2ϫ CH), 128.2 (CH), 127.2 (2ϫ CH), 126.9
δ = 156.8 (q, J = 36.0 Hz, C, NCOCF3), 139.9 (C), 135.5 (C), 135.4
(CH), 125.2 (CH), 122.7 (CH), 119.9 (CH2), 115.6 (CH2), 21.5
(C), 134.6 (CH), 131.2 (CH), 130.5 (CH), 130.1 (CH), 127.1 (CH), (CH3, Ar-CH3) ppm. MS: m/z = 326.20 [M + H+]. C19H19NO2S
120.8 (CH2), 118.2 (CH2), 116.1 (q, J = 287.0 Hz, C, NCOCF3),
54.1 (CH2), 34.5 (CH2) ppm. MS: m/z = 304.00 [M + H+].
(325.11): calcd. C 70.12, H 5.88, N 4.30; found C 70.21, H 5.81, N
4.23.
Eur. J. Org. Chem. 2011, 3514–3522
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3519

D. B. Ramachary, V. V. Narayana
FULL PAPER
Procedure E – Synthesis of 6af and 6bf: A 25 mL oven-dried round-
water and the aqueous layer was extracted with diethyl ether
bottomed flask equipped with a stirring bar was charged with diene
(2ϫ20 mL). The combined organic layers were dried (Na2SO4),
1af–1bf (0.25 mmol), pTSA (0.25 mmol, 47.5 mg) and Grubbs’ sec- filtered, and concentrated. Pure product 2bfa was obtained by col-
ond-generation catalyst H (21.22 mg, 0.025 mmol, 10 mol-%) in umn chromatography (silica gel, mixture of hexane/ethyl acetate).
dry CH2Cl2 (10 mL, 0.02 m) and the reaction mixture was stirred
1-Prop-2-ynyl-2,3-dihydro-1H-benzo[b]azepine (2bfb): Prepared by
under N2 at room temperature for 24 h. The crude reaction mixture
following procedure F, method C, and purified by column
was worked up with an aqueous solution of NaHCO3 and the
chromatography using EtOAc/hexane and isolated as a solid. IR
aqueous layer was extracted with CH2Cl2 (2ϫ20 mL). The com-
(neat): ν
= 3293 (CϵC–H), 2921, 1594, 1495, 1448, 1215, 752,
˜
max
1
bined organic layers were dried (Na2SO4), filtered, and concen-
trated. Pure products 6af–6bf were obtained by column chromatog-
raphy (silica gel, mixture of hexane/ethyl acetate).
670 cm–1. H NMR (CDCl3): δ = 7.17 (d, J = 7.2 Hz, 1 H), 7.15
(t, J = 8.0 Hz, 1 H), 7.01 (d, J = 8.0 Hz, 1 H), 6.86 (t, J = 7.2 Hz,
1 H), 6.40 (d, J = 12.0 Hz, 1 H, olefinic-H), 5.96 (td, J = 12.0,
4.4 Hz, 1 H, olefinic-H), 4.01 (d, J = 2.0 Hz, 2 H, NCH2CϵC-H),
3.29 (t, J = 5.2 Hz, 2 H), 2.57–2.56 (m, 2 H), 2.27 (t, J = 2.0 Hz,
1 H, NCH2CϵC-H) ppm. 13C NMR (CDCl3, DEPT-135): δ =
7-Chloro-2,5-dihydro-1H-benzo[b]azepine (6af): Prepared by follow-
ing procedure E and purified by column chromatography using
EtOAc/hexane and isolated as a solid. IR (neat): ν
= 3440 (N–
˜
max
H), 3060, 1502, 1411, 1261, 1143, 804 cm–1. H NMR (CDCl3): δ 149.4 (C), 133.4 (CH), 130.2 (CH), 130.0 (CH), 127.4 (CH), 126.9
1
= 7.04 (s, 2 H, Ar-H), 6.73 (d, J = 8.4 Hz, 1 H), 5.83–5.80 (m, 1 (C), 120.0 (CH), 115.3 (CH), 80.2 (C, NCH2CϵC-H), 71.9 (CH,
H, olefinic-H), 5.54 (d, J = 10.8 Hz, 1 H, olefinic-H), 3.76 (br. s, 2
H, NCH2), 3.44 (br. s, 2 H, ArCH2) ppm. 13C NMR (CDCl3,
DEPT-135): δ = 147.4 (C), 136.3 (C), 129.0 (CH), 127.2 (CH), 126.9
(CH), 126.6 (C), 125.4 (CH), 121.8 (CH), 48.1 (CH2), 32.8 (CH2)
ppm. MS: m/z = 180.10 [M + H+].
NCH2CϵC-H), 50.6 (CH2, NCH2CϵC-H), 42.4 (CH2), 33.6 (CH2)
ppm. MS: m/z = 184.00 [M + H+].
Procedure G – Gold-Catalyzed Cascade Hydroamination and Diels–
Alder Reactions
Method A – Synthesis of 4ab and 4eb–4gb: Compounds 3ab and
3eb–3gb (0.1 mmol) were added to mixture of [AuCl(PPh3)]
(2.42 mg, 0.005 mmol, 5 mol-%) and AgOTf (1.28 mg, 0.005 mmol,
5 mol-%) in dry toluene (2 mL, 0.05 m), taken in a sealed glass tube
and the mixture is heated at 100 °C under N2 for 6 to 24 h. The
crude reaction mixture was purified by column chromatography
(silica gel, mixture of hexane/ethyl acetate). Pure products 4ab and
4eb–4gb were obtained in moderate yields.
Procedure F – Base-Induced Double-Bond-Isomerization Reactions
Method A – Synthesis of 2af–2fh: A 10 mL oven-dried round-bot-
tomed flask equipped with a stirrer bar was charged with 6af–6fh
(0.2 mmol) and dry DMSO (4 mL, 0.05 m) before potassium tert-
butoxide (67.3 mg, 0.6 mmol, 3.0 equiv.) was added at 0 °C. The
reaction mixture was stirred at 25 °C for 1 h. The crude reaction
mixture was worked up with water and the aqueous layer was ex-
tracted with diethyl ether (2ϫ20 mL). The combined organic layers
were dried (Na2SO4), filtered, and concentrated. Pure products
2af–2fh were obtained by column chromatography (silica gel, mix-
ture of hexane/ethyl acetate).
6-Chloro-2-methyl-1-(toluene-4-sulfonyl)-1,2-dihydroquinoline (4ab):
Prepared by following procedure G, method A, and purified by
column chromatography using EtOAc/hexane and isolated as a li-
1
quid. IR (neat): ν
= 1473, 1345, 1091, 1037, 737, 661 cm–1. H
˜
max
7-Chloro-2,3-dihydro-1H-benzo[b]azepine (2af): Prepared by follow-
ing procedure F, method A, and purified by column chromatog-
NMR (CDCl3): δ = 7.68 (d, J = 8.8 Hz, 1 H), 7.28 (d, J = 8.4 Hz,
2 H), 7.24 (dd, J = 8.4, 2.4 Hz, 1 H), 7.09 (d, J = 8.0 Hz, 2 H),
6.94 (d, J = 2.4 Hz, 1 H), 5.92 (d, J = 9.6 Hz, 1 H, olefinic-H),
5.70 (dd, J = 9.6, 5.6 Hz, 1 H, olefinic-H), 4.94 (quintet, J = 6.4 Hz,
1 H, NCH), 2.35 (s, 3 H, Ar-CH3), 1.16 (d, J = 6.8 Hz, 3 H,
CHCH3) ppm. 13C NMR (CDCl3, DEPT-135): δ = 143.5 (C), 136.0
raphy using EtOAc/hexane and isolated as a solid. IR (neat): ν
˜
max
1
= 3391 (N–H), 2916, 1593, 1566, 1491, 1251, 1089, 767 cm–1. H
NMR (CDCl3): δ = 7.08 (d, J = 2.4 Hz, 1 H), 6.94 (dd, J = 8.4,
2.4 Hz, 1 H), 6.54 (d, J = 8.4 Hz, 1 H), 6.25 (d, J = 12.0 Hz, 1 H,
olefinic-H), 5.96–5.49 (m, 1 H, olefinic-H), 4.32 (s, 1 H, N-H), 3.30 (C), 131.8 (C), 131.1 (C & CH), 129.7 (C), 129.2 (2ϫ CH), 129.1
(t, J = 4.8 Hz, 2 H), 2.57–2.53 (m, 2 H) ppm. 13C NMR (CDCl3, (CH), 127.8 (CH), 127.1 (2ϫ CH), 125.9 (CH), 122.7 (CH), 51.0
DEPT-135): δ = 147.3 (C), 132.3 (CH), 131.2 (CH), 128.8 (CH), (CH), 21.5 (CH3, Ar-CH3), 19.8 (CH3) ppm. MS: m/z = 334.01 [M
126.9 (CH), 125.4 (C), 123.6 (C), 118.4 (CH), 44.6 (CH2), 34.7 + H+]. C17H16ClNO2S (333.05): calcd. C 61.16, H 4.83, N 4.20;
(CH2) ppm. MS: m/z = 179.95 [M + H+].
found C 61.22, H 4.78, N 4.32. HRMS: m/z = 356.0485 [M + Na],
calcd. for C17H16NO2SNa 356.0488.
Method B – Synthesis of 2bfa: A 10 mL oven-dried round-bottomed
flask equipped with a stirrer bar was charged with 6bf (0.2 mmol)
and dry DMSO (4 mL, 0.05 m) before potassium tert-butoxide
(67.3 mg, 0.6 mmol, 3.0 equiv.) was added at 0 °C. After 1 h, allyl
bromide (a; 48.4 mg, 0.4 mmol, 2 equiv.) was added to the reaction
mixture. The reaction mixture was stirred at 25 °C for another 3 h.
The crude reaction mixture was worked up with water and the
aqueous layer was extracted with diethyl ether (2ϫ20 mL). The
Method B – Synthesis of 4aa–4ga, 5aa–5ga, and 5ad: Compounds
3aa–3ga and 3ad (0.1 mmol) were added to mixture of
[AuCl(PPh3)] (2.42 mg, 0.005 mmol, 5 mol-%) and AgOTf
(1.28 mg, 0.005 mmol, 5 mol-%) in dry toluene (2 mL, 0.05 m),
placed in a sealed glass tube, and the mixture was heated at 100 °C
under N2 for 6–24 h. Purification of crude reaction mixtures by
column chromatography (silica gel, mixture of hexane/ethyl acet-
combined organic layers were dried (Na2SO4), filtered, and concen- ate) gave products 4aa–4ga, 5aa–5ga, and 5ad in moderate to good
trated. Pure product 2bfa was obtained by column chromatography
yields.
(silica gel, mixture of hexane/ethyl acetate).
Ethyl 6-Chloro-2-methyl-2H-quinoline-1-carboxylate (4aa): Pre-
pared by following procedure G, method B, and purified by column
chromatography using EtOAc/hexane and isolated as a liquid. IR
Method C – Synthesis of 2bfb: A 10 mL oven-dried round-bot-
tomed flask equipped with a stirrer bar was charged with 6bf
(0.2 mmol) and dry DMSO (4 mL, 0.05 m) before potassium tert-
butoxide (67.3 mg, 0.6 mmol, 3.0 equiv.) was added at 0 °C. After
(neat): νmax = 1719 (N–C=O), 1671, 1498, 1216, 1043, 732 cm–1. 1H
˜
NMR (CDCl3): δ = 7.57–7.55 (m, 1 H), 7.18 (dd, J = 8.8, 2.8 Hz, 1
1 h, propargyl bromide (b; 47.5 mg, 0.4 mmol, 2 equiv.) was added H), 7.07 (d, J = 2.4 Hz, 1 H), 6.38 (d, J = 9.6 Hz, 1 H, olefinic-H),
to the reaction mixture. The reaction mixture was stirred at 25 °C
for another 18 h. The crude reaction mixture was worked up with
6.08 (dd, J = 9.6, 6.0 Hz, 1 H, olefinic-H), 5.13 (quintet, J = 6.4 Hz,
1 H, NCH), 4.33–4.24 (m, 2 H, OCH2CH3), 1.34 (t, J = 7.2 Hz, 3
3520
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3514–3522

Medicinally Important Heterocycles
H, OCH2CH3), 1.12 (d, J = 6.8 Hz, 3 H, CHCH3) ppm. 13C NMR tific and Industrial Research (CSIR) (New Delhi) for a research
(CDCl3, DEPT-135): δ = 154.0 (C, N-C=O), 132.8 (C), 132.0 (CH), fellowship.
129.0 (C), 128.4 (C), 127.2 (CH), 125.8 (CH), 125.7 (CH), 123.3
(CH), 62.2 (CH2, OCH2CH3), 48.9 (CH), 18.5 (CH3), 14.5 (CH3,
OCH2CH3) ppm. MS: m/z = 252.25 [M + H+]. C13H14ClNO2
(251.07): calcd. C 62.03, H 5.61, N 5.56; found C 62.13, H 5.58, N
5 . 6 5 . H R M S : m / z = 2 7 4 . 0 6 1 1 [ M + N a ] , c a l c d . f o r
C13H14ClNO2Na 274.0611.
[1] a) H. Ogawa, H. Yamashita, K. Kondo, Y. Yamamura, H. Mi-
yamoto, K. Kan, K. Kitano, M. Tanaka, K. Nakaya, S. Nama-
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Ethyl 2-Chloro-6-(5-chloro-2-ethoxycarbonylaminophenyl)-7-methyl-
6a,7,8,10a-tetrahydro-6H-phenanthridine-5-carboxylate (5aa): Pre-
pared by following procedure G, method B, and purified by column
chromatography using EtOAc/hexane and isolated as a solid. IR
(neat): ν
= 1726 (N–C=O), 1682 (N–C=O), 1481, 1401, 1221,
˜
max
1053, 739 cm–1. 1H NMR (CDCl3): δ = 9.26 (s, 1 H, N-H), 7.69
(br. d, J = 5.2 Hz, 1 H), 7.33 (d, J = 2.0 Hz, 1 H), 7.26 (dd, J =
8.8, 2.4 Hz, 1 H), 7.21 (dd, J = 8.8, 2.4 Hz, 1 H), 7.10 (d, J =
8.4 Hz, 1 H), 6.46 (d, J = 2.4 Hz, 1 H), 6.14 (br. d, J = 10.4 Hz, 1
H, olefinic-H), 6.03–5.99 (m, 1 H, olefinic-H), 5.32 (d, J = 10.4 Hz,
1 H, NCH), 4.30 (q, J = 7.2 Hz, 2 H, OCH2CH3), 4.26–4.13 (m, 2
H, OCH2CH3), 3.15 (d, J = 10.0 Hz, 1 H), 2.15–2.09 (m, 1 H),
2.05–1.95 (m, 1 H), 1.77–1.65 (m, 2 H), 1.38 (t, J = 7.2 Hz, 3 H,
OCH2CH3), 1.23 (t, J = 7.2 Hz, 3 H, OCH2CH3), 0.61 (d, J =
6.4 Hz, 3 H, CHCH3) ppm. 13C NMR (CDCl3, DEPT-135): δ =
155.8 (C, N-C=O), 154.6 (C, N-C=O), 139.4 (2ϫ C), 136.3 (CH),
134.7 (C), 134.6 (C), 131.6 (C), 130.0 (CH), 129.4 (C), 128.2 (CH),
127.4 (CH), 127.1 (CH), 126.5 (CH), 123.4 (2ϫ CH), 62.8 (CH2,
OCH2CH3), 61.2 (CH2, OCH2CH3), 56.7 (CH), 54.4 (CH), 39.1
(CH), 34.9 (CH2), 34.5 (CH), 18.8 (CH3), 14.7 (CH3, OCH2CH3),
14.3 (CH3, OCH2CH3) ppm. MS: m/z = 503.30 [M + H+].
C26H28Cl2N2O4 (502.14): calcd. C 62.03, H 5.61, N 5.56; found C
62.18, H 5.67, N 5.46. HRMS: m/z = 525.1323 [M + Na], calcd.
for C26H28Cl2N2O4Na 525.1324.
[4] CCDC-798519 (for 3ac) and -798520 (for 5aa) contain the sup-
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be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
See the Supporting Information for crystal structures.
N-[2-(5-Acetyl-2-chloro-7-methyl-5,6,6a,7,8,10a-hexahydrophen-
anthridin-6-yl)-4-chlorophenyl]acetamide (5ad): Prepared by follow-
ing procedure G, method B, and purified by column chromatog-
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raphy using EtOAc/hexane and isolated as a solid. IR (neat): ν
˜
max
= 2917, 1692 (N–C=O), 1637, 1603, 1482, 1298, 1038, 737 cm–1.
1H NMR (CDCl3): δ = 10.38 (s, 1 H, N-H), 7.82 (d, J = 8.8 Hz, 1
H), 7.39 (d, J = 1.6 Hz, 1 H), 7.31 (dd, J = 8.8, 2.4 Hz, 1 H), 7.20
(dd, J = 8.8, 2.4 Hz, 1 H), 6.92 (d, J = 8.0 Hz, 1 H), 6.34 (d, J =
2.0 Hz, 1 H), 6.13 (d, J = 8.8 Hz, 1 H, olefinic-H), 6.03–5.99 (m, 1
H, olefinic-H), 5.57 (d, J = 8.4 Hz, 1 H, NCH), 3.09 (d, J =
10.8 Hz, 1 H), 2.32 (s, 3 H, COCH3), 2.16–2.08 (m, 1 H), 2.08 (s,
3 H, COCH3), 1.97–1.94 (m, 1 H), 1.76–1.65 (m, 2 H), 0.59 (d, J
= 6.4 Hz, 3 H, CHCH3) ppm. 13C NMR (CDCl3, DEPT-135): δ =
171.0 (C, N-C=O), 168.9 (C, N-C=O), 140.8 (C), 135.5 (C), 135.0
(C), 134.6 (C), 133.4 (C), 130.5 (CH), 129.6 (C), 128.3 (CH), 127.3
(CH), 127.1 (CH), 127.0 (CH), 126.4 (CH), 124.2 (CH), 122.9
(CH), 55.7 (CH), 53.8 (CH), 39.2 (CH), 34.8 (CH2), 34.6 (CH),
24.3 (CH3, COCH3), 22.4 (CH3, COCH3), 19.0 (CH3) ppm. MS:
m/z = 443.35 [M + H+]. C24H24Cl2N2O2 (442.12): calcd. C 65.02,
H 5.46, N 6.32; found C 65.12, H 5.51, N 6.23. HRMS: m/z =
465.1112 [M + Na], calcd. for C24H24Cl2N2O2Na 465.1113.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, synthesis of starting materials, X-
ray crystal structures, and analytical data for all new compounds.
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Acknowledgments
We thank the Department of Science and Technology (DST) (New
Delhi) for financial support. V. V. N. thanks the Council of Scien-
Eur. J. Org. Chem. 2011, 3514–3522
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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D. B. Ramachary, V. V. Narayana
FULL PAPER
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Received: January 12, 2011
Published Online: May 24, 2011
3522
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3514–3522