Synthesis of nitrogen-containing heterocycles via ring-closing ene-ene and ene-yne metathesis reactions: An easy access to 1- and 2-benzazepine scaffolds and five- and six-membered lactams

Article abstract of DOI:10.1055/s-0032-1317352

Novel regioselective ring closing ene-yne metathesis provided an efficient access to different substituted 1-benzazepine scaffolds. The reported synthetic approach could also be used as a powerful tool for the selective formation of a highly functionaliza

Full text of DOI:10.1055/s-0032-1317352

PAPER
▌3523
paper
Synthesis of Nitrogen-Containing Heterocycles via Ring-Closing Ene-Ene and
Ene-Yne Metathesis Reactions: An Easy Access to 1- and 2-Benzazepine
Scaffolds and Five- and Six-Membered Lactams
Nitrogen-Containing Heterocycles
Erica Benedetti,*a,b Michela Lomazzi,a Francesco Tibiletti,a Jean-Philippe Goddard,b Louis Fensterbank,b
Max Malacria,b Giovanni Palmisano,a Andrea Penoni*a
a
Dipartimento di Scienza e Alta Tecnologia, Università degli Studi dell’Insubria, via Valleggio 11, 22100, Como, Italy
Fax +39(031)2386449; E-mail: andrea.penoni@uninsubria.it
b
Institut Parisien de Chimie Moléculaire (UMR CNRS 7201) – FR 2769 UPMC Université Paris 06, C. 229, 4 Place Jussieu, 75005 Paris,
France
Received: 23.07.2012; Accepted after revision: 14.09.2012
achieve by conventional ways, or previously unattainable.
Abstract: Novel regioselective ring closing ene-yne metathesis
Thus, in the last decade, ring-closing ene-ene metathesis
provided an efficient access to different substituted 1-benzazepine
(RCM) as well as ring-closing ene-yne metathesis (RC-
EYM) have shown an explosion of their application being
scaffolds. The reported synthetic approach could also be used as a
powerful tool for the selective formation of a highly functionaliz-
able 2-benzazepine core. This synthetic protocol was even proved nicely exploited for the synthesis of complex molecules
and natural products.7,8
to be an efficient way to obtain a functionalizable benzazocine
derivative. By modifying the structure of the starting materials, the
optimized cyclization finally proved to be a suitable technique to
obtain five- and six-membered lactams, enhancing the synthetic ap-
O
F
OH
plication of our method. Five- and six-membered lactams were ef-
ficiently prepared by ring-closing metathesis involving the loss of
ethylene moiety and affording highly functionalizable compounds
showing both electron-withdrawing substituents and electron-donor
groups.
O
N
N
H2N
N
N
F
Key words: ring closing ene-yne metathesis, ring closing ene-ene
metathesis, Grubbs catalysts, nitrogen heterocycles, regioselective
reactions, benzazepine scaffolds, lactams
I
II
OEt
Me
N
MeO
OMe
O
Many natural and synthetic seven-membered nitrogen
heterocycles are currently an object of sustained interest
due to the vast range of their biological activities1 and, in
particular, benzo-fused dia-, thia- and oxazepines have
been the focus of much synthetic efforts in the past de-
cades.2 Surprisingly, the 1H-benzo[b]azepine (1-benzaze-
pine) scaffold as well as its congener 1H-benzo[c]azepine
(2-benzazepine) have been only scarcely explored, de-
spite both ring systems represent crucial pharmacophores
in drug discovery (Figure 1).3,4 The biological relevance
of benzazepines recently prompted organic chemists to
discover novel methodologies for the synthesis of such
ring systems.5
OH
O
HO
O
N
OMe
H
N
Ph
III
IV
Figure 1 Representative benzazepine-based biologically active
compounds: a 5-lipoxygenase inhibitor I, an inhibitor of N-type cal-
cium channels II, a molecule used for the treatment of Alzheimer’s
disease III, and a muscarin M3 antagonist IV
Although RCM has already proved to be an efficient
method to access the benzazepine motif,9 syntheses rely-
ing on RCEYM have rarely been reported.10 We describe
herein new regioselective RCEYM, in which different
functionalized 1-benzazepines were formed. Our conve-
nient synthetic protocol also allows for the easy formation
of a 2-benzazepine framework, extending the general
scope of the reaction. By tuning the structure of the start-
ing materials, the optimized cyclization also proved to be
a straightforward route to five- and six-membered lac-
tams. Finally, we demonstrate with representative trans-
formations that the primary metathesis products can be
further functionalized, thus achieving higher molecular
complexity.
Medium-sized carbo- and heterocycles are difficult to ob-
tain and most of the classical strategies, which allow their
formation, are hampered by enthalpic and entropic fac-
tors.6 In the last few years, however, alkene metathesis has
dramatically emerged as a versatile synthetic technique.
Since the discovery of stable, reactive, and highly func-
tional group tolerant catalysts (Figure 2), this multiple-
bond reorganization has provided organic chemists with a
powerful tool to access molecules, which are difficult to
SYNTHESIS 2012, 44, 3523–3533
Advanced online publication: 09.10.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1317352; Art ID: SS-2012-Z0606-OP
© Georg Thieme Verlag Stuttgart · New York

3524
E. Benedetti et al.
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the formation of N-protected 1,8-enynes 4a–j was readily
PCy3
accomplished under standard conditions in good yields.12
PCy3
N
N
N
N
Mes
Mes Mes
Mes
Cl
Cl
Cl
Cl
Ru
Ph
Ph
Cl
Cl
Ru
A different kind of aza-1,8-enyne substrate was investi-
gated with the aim of exploring a wide screen of potential
precursors for seven-membered nitrogen-containing het-
erocycles. The synthesis of product 8 is outlined in
Scheme 2 and started with the commercially available 2-
iodoaniline (5). Thus, Sonogashira coupling and subse-
quent protodesilylation were readily effected and the en-
suing alkyne 6 was submitted to N-alkylation with 4-
bromobutene to give compound 7, followed by acylation
with acryloyl chloride leading to 8 in 16% (unoptimized)
yield over all four steps.
Ru
Ru
Ph
Cl
Cl
PHCy3
PCy3
Ph
Ph
PCy3
PCy3
A
B
A'
B'
Grubbs catalyst
(second generation)
Grubbs catalyst
(first generation)
PCy3
N
N
Mes
Mes
Cl
Ru
Cl
Cl
Ru
O
O
Cl
C
D
1)
SiMe3
PdCl2(PPh3)2
CuI, Et3N, THF
Hoveyda–Grubbs catalyst
(first generation)
Hoveyda–Grubbs catalyst
(second generation)
NH2
NH2
2) TBAF
I
i-Pr
t-Bu
i-Pr
N
5
6 (quant.)
Br
O
Mo
Ph
O
K2CO3, DMF
70 °C, 12 h
t-Bu
O
O
E
H
N
Cl
N
(S)-Schrock–Hoveyda catalyst
Et3N
CH2Cl2
Figure 2 Commercially available metathesis catalysts
8 (48%)
7 (34%)
Preparation of the Azaenynes and Azadienes
Scheme 2 Synthesis of a 5-aza-1,8-enyne (compound 8)
Due to the extraordinary versatility of ene-yne systems,
our investigations were started by developing a suitable
strategy to access RCEYM precursors (Scheme 1). Start-
ing from N-allylanilines 1a–d, a sigmatropic aza-Claisen
rearrangement through the agency of a Lewis acid
(BF3·OEt2 in refluxing p-xylene) proved to be the better
way to obtain 2-allylanilines 2a–d.11 This compound was
subsequently alkylated with propargyl bromide in the
presence of K2CO3 to give the intermediate ene-yne sub-
strates 3a–d in 22–32% (unoptimized) overall yields and
To further document the scope and generality of our syn-
thetic procedure, the behavior of a 4-aza-1,8-enyne 12
connected to an aromatic ring was studied to obtain a 2-
benzazepine framework. The substrate 12 was prepared
from commercially available 2-iodobenzaldehyde (9a) by
a sequence of reactions (Scheme 3) commencing with
two-step reductive amination with allylamine giving the
secondary amine 10a, followed by acylation with acryloyl
Scheme 1 Synthesis of different 6-aza-1,8-enynes
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Nitrogen-Containing Heterocycles
3525
11a X = 2-I
11b X = H
11c X = 4-NO2
11d X = 2-NO2
11e X = 4-Br
O
1)
NH2
MgSO4, CHCl3
O
CHO
N
Cl
Et3N, CH2Cl2
H
N
2) NaBH3(CN)
X
X
X
MeOH, 0 °C to r.t.
10a–e (quant.)
11a–e (48–90%)
9a–e
1)
SiMe3
PdCl2(PPh3)2
O
O
CuI, Et3N, THF
N
N
2) TBAF
I
12 (49%)
11a
Scheme 3 Synthesis of a 4-aza-1,8-enyne (compound 12)
chloride for the formation of 11a. Sonogashira coupling
of the resulting amide 11a to trimethylsilylacetylene fol-
lowed by desilylation provided 12 in 44% yield over all
five steps.
O
O
14a X = H
H
N
14b X = 4-I
14c X = 4-OMe
14e X = 3-Br
Cl
Et3N, CH2Cl2
N
X
X
To establish whether the crucial alkyne moiety had any
specific role, the previous starting materials were modi-
fied and redesigned as 11a–e, 14a–d, and 16a–e. Com-
pounds 14a–d were prepared by the reaction of the
corresponding N-allylanilines with acryloyl chloride.
Analogously amides 16a–e were obtained starting from of
N-(but-3-enyl)anilines by acylation with acryloyl chloride
(Scheme 4).
13a–e
14a–e (65–79%)
16a X = H
O
O
H
N
16b X = 4-Me
16c X = 4-OMe
16d X = 2-I
16e X = 4-I
Cl
N
X
Et3N, CH2Cl2
X
15a–e
16a–e (61–94%)
Because substrate 22 does not have an acryloyl moiety we
tried to obtain a compound showing more similarity with
12. All our attempts to synthesize the compound 20 start-
ing from compound 19 by a Sonogashira-type reaction
Scheme 4 Synthesis of 4-aza-1,6-dienes and 4-aza-1,7-dienes 14a–d
and 16a–e
1)
SiMe3
PdCl2(PPh3)2
O
O
O
CuI, Et3N, THF
N
N
I
19 (20%)
O
2) TBAF
O
20
ClCH2CH2Cl
N
H
O
Cl
I
O
I
HN
COOH
I
SOCl2
N
K2CO3, CH2Cl2
17
21 (80%)
18 (quant.)
SiMe3
PdCl2(PPh3)2
CuI, Et3N, THF
1)
O
N
2) TBAF
22 (63%)
Scheme 5 Synthesis of 4-aza-1,6-dienes (compounds 29, 32, and 33)
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E. Benedetti et al.
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Table 1 Catalyst Screeninga
were so far unfruitful (Scheme 5). This substrate could
give an interesting and correct example for a parallel
study to verify chemo- and regioselectivity of the entire
process.
O
O
O
O
catalyst (3 mol%)
toluene, N2
N
N
70 °C, 3 h
(0.05 M)
Starting from 2-iodobenzaldehyde (9a) a reductive ami-
nation reaction was run with but-3-enylamine hydrochlo-
ride and after treatment with NaBH3CN secondary amine
23 was isolated. Amide 24 was synthesized by reaction
with acryloyl chloride and converted into the yne 25 by
Sonogashira coupling with trimethylsilylacetylene
(Scheme 6).
26a
4a
Entry
Catalyst
Yield (%)b
1
2
3
4
5
A
B
C
D
E
n.r.c
21
Ring-Closing Ene-Yne and Ring-Closing Ene-Ene
Metathesis Reactions
n.r.c
45
Our attention was then turned to the optimization of the
cyclization conditions. Due to the wide variety of com-
mercially available catalysts, the selection of one over the
others can be a real challenge. Previous literature reports13
clearly showed that no single catalyst is the best for all
multiple-bond reorganizations. It is well known that
amines and basic functional groups reduce the efficiency
of catalysts in metathesis reaction due to the interactions
of the lone pair of electrons on nitrogen with the metal
center. Indeed, the reactivity of different metal complexes
was screened using compound 4a as model substrate (Ta-
ble 1, entries 1–5) and Hoveyda–Grubbs second-genera-
tion catalyst D quickly emerged as the best choice
affording the 1-benzazepine 26a in 45% yield.
n.r.c
a Reaction conditions: 0.2 mmol of substrate (0.05 M in toluene), 3
mol% of catalyst, 70 °C, inert atmosphere, 5 h.
b Isolated yield.
c No reaction.
gated by the reaction of compounds 4b and 4c. In both
cases, RCEYM afforded 26b and 26c in 39% and 57%
yield, respectively (Table 2, entries 1 and 2). Unlike pre-
cursors embodying an EWG on the nitrogen atom, ani-
lines 3a and 4d appeared reluctant to metathesis reaction
and only starting materials were recovered (Table 2, en-
tries 3 and 4). Surprisingly, when 4f and 4e were submit-
ted to the latter conditions, no signs of any product arising
from RCEYM could be detected in the crude reaction
mixture and only dimeric compounds 27a and 27b (i.e.,
tandem RCEYM/homo-CM products) were isolated in
51% and 43% yield, respectively (Figure 3).16 No traces of
this kind of by-products were detected by using other sub-
strates. The configuration of the newly formed exocyclic
double bond was predominantly E for both dimers as as-
Dichloromethane, a solvent frequently used in RCM, was
recently shown to greatly decrease the catalyst efficien-
cy,14 therefore toluene was used in all our experiments. A
temperature of 70 °C resulted to be the best compromise
between fast reaction rates, solvent loss, and precursor or
catalyst degradation. The substrate concentration also has
remarkable effects on RCM and RCEYM. As the ring size
increases from five to seven, more diluted solutions (typ-
ically in 0.2–0.05 M range) are needed to achieve com-
plete conversion of the starting materials.15
1
sessed by H NMR spectroscopy (narrow signals of the
olefinic protons at 5.86–5.69 ppm).
The scope of the cyclization was assessed using the N-
propargyl-2-allylanilines 3a, 4a–j, that is, differing in the
electronic and steric properties of the substituent located
on the nitrogen atom. The substituent effect was investi-
To our delight, reluctance of 4e and 4f to undergo RC-
EYM was overcome by running the reaction under an eth-
ylene atmosphere as suggested by Mori and co-workers17
O
1)
NH2⋅HCl
Na2SO4, CHCl3
O
CHO
I
N
Cl
H
N
2) NaBH3(CN)
Et3N, CH2Cl2
I
MeOH, 0 °C to r.t.
I
23 (quant.)
24 (87%)
9a
SiMe3
1)
PdCl2(PPh3)2
CuI, Et3N, THF
O
N
2) TBAF
25 (53%)
Scheme 6 Synthesis of a 5-aza-1,9-enyne (compound 25)
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Nitrogen-Containing Heterocycles
3527
Table 2 Substrate Scope of RCEYM Reactionsa (continued)
Entry Substrate
Product
Yield
(%)b
O
O
N
Bn
Bn
N
N
5
6
49d
N
O
O
4e
4f
26e
26f
Boc
N
Boc
N
27a
51d
N
O
O
N
O
N
7
8
9
46
39
53
N
4g
4h
26g
26h
27b
O
N
N
Figure 3 RCEYM by-products from compounds 4f and 4e
and the expected 3-vinyl benzazepines 26e and 26f were
successfully isolated in 49% and 51% yield, respectively
(Table 2, entries 5 and 6).
O
O
Table 2 Substrate Scope of RCEYM Reactionsa
N
N
Entry Substrate
Product
Yield
(%)b
Cl
Cl
4i
26i
Ts
Ts
N
N
O
O
1
39
N
N
10
27
4b
26b
26c
MeO
MeO
PhOC
COPh
N
4j
N
26j
a Reaction conditions: 0.2 mmol of substrate (0.05 M in toluene), 3
mol% of catalyst D, 70 °C, inert atmosphere, 5 h.
b Isolated yield.
2
3
4
57
nrc
nrc
4c
3
c nr = no reaction.
H
N
d Reaction conditions: 0.2 mmol of substrate (0.05 M in toluene), 3
mol% of catalyst D, 70 °C, ethylene atmosphere, 8 h.
H
N
For comparison purposes, the behavior of 4g featuring an
internal acryloyl moiety was also investigated. In princi-
ple, apart from homo-CM products, three different reac-
tion pathways have been envisaged: RCM (ene-enone)
was expected to give rise to a dihydrobenzazepinone skel-
eton while competing RCEYM (ene-yne) and RCEYM
(enone-yne) might also produce isomeric 1,3-diene incor-
porated in seven- and five-ring systems, respectively.
Treatment of 4g under our standard conditions furnished
Me
N
Me
N
4d
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3528
E. Benedetti et al.
PAPER
the corresponding N-acryloylbenzazepine 26g in 46% us the opportunity for subsequent chemistry and construc-
yield. No detectable quantities of either dihydrobenzaze- tion of polycyclic compounds (complexity generation by
pinones or RCEYM (enone-yne) products were found in post-metathesis transformations). Thus, for instance, the
the crude reaction mixtures. The observed selectivity fa- 1,3-diene subunit in 28 smoothly reacted with either di-
voring RCEYM (ene-yne) over other two reaction path- methyl acetylenedicarboxylate (DMAD) or maleimide
ways is believed to be controlled by high reactivity of the leading to the expected Diels–Alder adducts 30 and 31
C=C and C≡C bonds versus low reactivity of enone sub- (endo-adduct) in 66% and 58% yield, respectively. Like-
unit toward electrophilic Ru-carbene catalyst.18 Finally, wise, base-induced conjugate Michael addition with
we cannot exclude that the nature of catalyst, the concen- MeNO2 proceeded satisfactorily to the acryloyl moiety in
tration, the electronic/steric effects, and the s-cis/s-trans 28 delivering nitroalkane 32 in 43% yield without inter-
conformational ratio of the acrylamide precursor may also ference from the diene residue (Scheme 9).
play a relevant role.19–22
This cycloisomerization tolerates different substituents on
the aromatic ring of 1,8-enynes. Accordingly, exposure of
4h and 4i to the optimized reaction conditions provided
the expected 7-membered ring acrylamides 26h and 26i,
which were isolated in moderate yields (39% and 53%, re-
spectively). The OMe group in compound 4j interfered
with Ru=C fragment of the catalyst, thereby explaining
the low 27% yield of 26j (Table 2, entry 10).
O
O
DMAD
toluene, N2
N
N
120 °C, 4 h
(0.5 M)
66%
CO2Me
CO2Me
28
30
These findings prompted us to investigate the fate of a
new substrate, compound 8, featuring a 5-aza-1,8-enyne
framework (instead of the earlier 6-aza-1,8-enyne) under
our RCEYM conditions. Exposure of 8 to catalyst D (3
mol%) in toluene (0.02 M) at 70 °C for two hours led to
the smooth formation of the expected 1,3-diene 28 in 83%
isolated yield (Scheme 7).
O
O
N
maleimide
toluene, N2
N
H
H
O
120 °C, 4 h
(0.5 M)
58%
NH
O
H
O
O
28
31
catalyst D (3 mol%)
toluene, N2
N
N
70 °C, 2 h
(0.02 M)
O
O
MeNO2
NaH, N2
N
N
O2N
DMF, r.t., 2 h
43%
8
28 (83%)
Scheme 7 Synthesis of 1-benzazepine scaffold 28 via RCEYM
28
32
Gratifyingly, when 12 was subjected to our metathesis
conditions it cyclized in a manner analogous to that en-
countered earlier (i.e., 8 → 28) thereby generating the 2-
benzazepine 29 in 74% yield (Scheme 8).
Scheme 9 Post-metathesis functionalizations
These orthogonal functionalizations emphasize the versa-
tility of these heterocyclic scaffolds, attesting their poten-
tial as building blocks for the synthesis of more complex
molecules through further reactions after ring-closing
process.23 Again and as mentioned earlier, in all the scru-
tinized examples (i.e., 4g–j, 8, and 12) the acryloyl moiety
appeared dormant toward the metathetical process and the
regiochemistry was dictated by RCEYM (ene-yne) pro-
cess such that benzazepines (26g–j, 28, and 29) were the
exclusive products of the ring-closing step.
O
catalyst D (3 mol%)
O
N
toluene, N2
N
70 °C, 2 h
(0.02 M)
12
29 (74%)
Other precursors of metathesis reactions without an al-
kyne functional group were used in the same reaction con-
ditions. Differently from the latter examples these
compounds were tested in ring-closing metathesis proce-
dures observing the participation of the C=C bond from
the acryloyl moiety to the reaction. Gratifyingly, excellent
Scheme 8 Synthesis of 2-benzazepine scaffold 29 via RCEYM
The availability of the corresponding benzazepines 26g–
j, 28, and 29, which incorporate, at least, two points of
molecular diversity (i.e., 1,3-diene and acrylamide) gave
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Nitrogen-Containing Heterocycles
3529
Table 3 Synthesis of Pyrrolone and Pyridinone Products via RCMa
(continued)
regiocontrol in the ring-closing metathesis was achieved
when these precursors were subjected to the optimized set
of reaction conditions and five- and six-membered lac-
tams 33a–e, 34a–d, and 35a–e were the exclusive prod-
ucts of reaction (Table 3, entries 1–14).24
Entry Substrate
Product
Yield
(%)b
Table 3 Synthesis of Pyrrolone and Pyridinone Products via RCMa
O
N
N
8
56
O
Entry Substrate
Product
Yield
(%)b
MeO
MeO
34c
14c
O
O
N
O
N
Br
N
1
95
I
Br
N
I
9
80
94
93
O
33a
33b
11a
11b
34d
O
14d
O
O
N
O
N
2
3
4
5
98
96
92
95
N
O
N
10
11
35a
35b
O
16a
16b
O
N
N
O
O2N
N
O2N
N
33c
11c
O
O
N
N
O
O
NO2
NO2
N
N
12
13
14
90
43
86
33d
11d
MeO
MeO
O
O
35c
16c
N
N
O
O
Br
Br
N
I
N
I
33e
11e
O
35d
16d
N
N
O
6
7
73
91
O
O
O
N
34a
N
14a
I
I
35e
N
16e
N
a Reaction conditions: 0.2 mmol of substrate (0.05 M in toluene), 3
mol% of catalyst D, 70 °C, inert atmosphere, 1 h.
b Isolated yield.
O
I
I
34b
14b
Substrate 19 was submitted to cyclization condition and
the imide 36 was produced in quantitative yield. An ex-
periment carried out on compound 22, revealed the forma-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3523–3533

3530
E. Benedetti et al.
PAPER
tion of the dihydropyrrole derivative 37 leaving the C≡C precursors and tolerated different functional groups on ar-
bond as a spectator substituent. RCEYM on compound 22 omatic rings. The ensuing products are appropriately
did not occur leaving the place to the efficient RCM be- functionalized for further orthogonal elaboration (i.e., ei-
tween the two allyl groups (Scheme 10).
ther via Diels–Alder reactions or Michael addition). By
modifying the structure of the starting materials, ring-
closing ene-ene metathesis also allowed the easy forma-
tion of five- and six-membered lactams. Work is under-
way in this lab to obtain other heterocyclic scaffolds by
metathesis procedures and to apply them in the total syn-
thesis of natural products and analogues of biological in-
terest.
O
O
O
O
catalyst D (3 mol%)
toluene, N2
N
N
70 °C, 2 h
(0.02 M)
I
I
19
36 (quant.)
O
O
catalyst D (3 mol%)
All metathesis reactions were carried out under N2 or ethylene in
oven-dried glassware. All substituted anilines and aldehydes were
purchased from Sigma-Aldrich Chemical Co. and were used with-
out further purification. Distilled solvents were used for all reac-
tions. TLC was performed on Macherey-Nagel polygram silica gel
with fluorescent indicator UV254. Carlo Erba reagents silica gel 60A
(70–200 μm) was employed for column chromatography. The melt-
ing points reported were measured with a Gallenkamp melting point
apparatus and are uncorrected. NMR spectra were recorded at 298
K in CDCl3 solutions (unless otherwise stated) on a Bruker Avance
toluene, N2
N
N
70 °C, 2 h
(0.02 M)
22
37 (49%)
Scheme 10 Synthesis of five-membered ring products 36 and 37
1
400 MHz spectrometer operating at 400 MHz for H and at 101
The amide 24 is another good reactant for the RCM pro-
cedure to form a six-membered lactam 38 in 76% yield
(Scheme 11).
MHz for 13C NMR. Chemical shifts are given in parts per million,
referenced to the residual proton resonance of the solvents (δ = 7.26
for CDCl3) or to the residual carbon resonance of the solvent (δ =
77.16 for CDCl3). GC-MS analyses were run on Shimadzu GC-MS-
QP5000. IR spectra were obtained using the Nicolet Magna-IR
Spectrometer 550. Chemical ionization mass spectra (+ve mode)
were performed on a Finnigan-MAT TSQ70 with isobutane as the
reactant gas. Elemental analyses were performed on a Perkin-Elmer
Series II CHNS/O Analyzer 2400.
O
catalyst D (3 mol%)
O
N
toluene, N2
N
70 °C, 2 h
(0.02 M)
I
I
Spectroscopic characterization of all the compounds used as precur-
sors and representative procedures for the preparation of the sub-
strates used in metathesis reaction as starting materials are reported
in the Supporting Information. This also includes experimental de-
tails and discussions on the unsuccessful results.
24
38 (76%)
O
catalyst D (3 mol%)
O
N
toluene, N2
Representative procedures RP1 (Claisen rearrangement), RP2 (al-
kylation reactions), and RP3 (acylation reactions) are described in
the Supporting Information.
N
70 °C, 2 h
(0.02 M)
Metathesis Reactions; Ethyl 3-Vinyl-2,5-dihydro-1H-ben-
zo[b]azepine-1-carboxylate (26a); Representative Procedure 4
(RP4)
25
39 (69%)
Compound 4a (0.08 g, 0.33 mmol) was dissolved in toluene (15
mL) at r.t. under N2 atmosphere. After bubbling N2 into the solution
for 10 min, catalyst D (0.006 g, 0.01 mmol) was added. The solution
was warmed at 70 °C and stirred for 3 h. At the end of the reaction,
the solvent was removed under reduced pressure and the residue
was purified by silica gel chromatography (EtOAc–hexane, 1:9) af-
fording the desired product as a yellow oil (36 mg, 0.15 mmol,
45%).
Scheme 11 Synthesis of lactam 38 and of azocine derivative 39
A further study to investigate the ability of the catalytic
system to obtain a RCEYM reaction leaving again the ac-
ryloyl moiety as a spectator ligand was run on a 1,9-enyne
substrate (compound 25). The enyne 25 was prepared, as
stated before, by a Sonogashira reaction on substrate 24.
Analogously to the reactions for the achievement of ben-
zazepine ring, compound 25 gave the accomplishment of
the benzazocine derivative 39 in 69% yield and no traces
of six-membered lactam were detected (Scheme 11). The
procedure seems to be a general protocol for the prepara-
tion of medium-large nitrogen-containing heterocycles.
IR (neat): 3396, 2979, 2932, 1701, 1495, 1406, 1306, 1239, 1172,
1050, 887, 766 cm–1.
1H NMR (373 K): δ = 7.40–7.16 (m, 4 H), 6.31 (dd, J = 18.0, 11.2
Hz, 1 H), 5.93 (dd, J = 6.0, 5.3 Hz, 1 H), 5.12 (d, J = 17.8 Hz, 1 H),
5.00 (d, J = 11.1 Hz, 1 H), 4.52 (br s, 2 H), 4.22 (dd, J = 14.0, 7.1
Hz, 2 H), 3.51 (d, J = 5.3 Hz, 2 H), 1.30–1.18 (m, 3 H).
13C NMR: δ = 155.9 (C), 141.2 (C), 139.1 (C), 138.8 (CH), 135.8
(C), 128.4 (CH), 127.9 (CH), 127.7 (CH), 127.6 (CH), 127.3 (CH),
111.3 (CH2), 61.9 (CH2), 47.1 (CH2), 31.9 (CH2), 14.8 (CH3).
In summary, we have developed a regioselective ring-
closing ene-yne metathesis (RCEYM) for the synthesis of
further functionalizable benzazepine scaffolds. The cycli-
zations were effective for a broad range of N-substituted
GC-MS (EI): m/z = 243, 214, 170, 154, 130, 115, 103, 77, 65.
Anal. Calcd for C15H17NO2 (243.31): C, 74.05; H, 7.04; N, 5.76.
Found: C, 74.12; H, 5.10; N, 5.79.
Synthesis 2012, 44, 3523–3533
© Georg Thieme Verlag Stuttgart · New York

PAPER
Nitrogen-Containing Heterocycles
3531
1-(5-Vinyl-2,3-dihydro-1H-benzo[b]azepin-1-yl)prop-2-en-1-
one (28)
Substrate 28 was synthesized, following the RP4, from compound
8 (74.3 mg, 0.33 mmol) and was isolated (eluent for chromatogra-
phy: EtOAc–hexane, 4:6) as a brown solid (61.7 mg, 0.27 mmol,
83%); mp 57 °C.
IR (neat): 3099, 2918, 1686, 1492, 1374, 1210, 1144, 991, 811 cm–1.
1H NMR: δ = 7.61 (d, J = 8.6 Hz, 2 H), 7.45 (d, J = 8.7 Hz, 2 H),
7.15 (d, J = 5.3 Hz, 1 H), 6.20 (d, J = 4.9 Hz, 1 H), 4.35 (s, 2 H).
13C NMR: δ = 142.5 (CH), 138.9 (C), 137.9 (CH), 129.1 (2 CH),
120.4 (2 CH), 110.0 (C), 87.4 (C), 52.9 (CH2).
IR (neat): 3088, 3027, 2927, 2878, 1652, 1408, 1216, 1073, 979,
904, 774 cm–1.
GC-MS (EI): m/z = 286, 256, 230, 203, 158, 130, 90, 76, 63, 50, 39,
27.
1H NMR: δ = 7.45–7.31 (m, 3 H), 7.19–7.09 (m, 1 H), 6.47 (dd, J =
17.5, 10.8 Hz, 1 H), 6.26 (dd, J = 16.8, 2.0 Hz, 1 H), 6.14 (t, J = 7.1
Hz, 1 H), 5.83 (dd, J = 16.8, 10.3 Hz, 1 H), 5.42 (dd, J = 10.3, 2.0
Hz, 1 H), 5.17 (d, J = 17.5 Hz, 1 H), 5.09 (d, J = 10.9 Hz, 1 H), 4.73
(td, J = 13.1, 5.4 Hz, 1 H), 3.53 (ddd, J = 12.8, 6.2, 2.1 Hz, 1 H),
2.32–2.27 (m, 1 H), 2.19–2.08 (m, 1 H).
13C NMR: δ = 166.2 (C), 140.4 (C), 139.7 (C), 137.4 (CH), 136.3
(C), 129.9 (CH), 129.8 (CH), 129.7 (CH), 129.2 (CH), 128.4 (CH),
127.9 (CH), 127.1 (CH2), 115.1 (CH2), 53.3 (CH2), 25.4 (CH2).
Anal. Calcd for C10H8INO (285.08): C, 42.13; H, 2.83; N, 4.91.
Found: C, 41.19; H, 3.03; N, 4.93.
1-Phenyl-5,6-dihydropyridin-2(1H)-one (35a)
Substrate 35a was synthesized, following the RP4, from compound
16a (60.3 mg, 0.3 mmol) and was isolated (EtOAc–hexane, 7:3) as
a brown solid (48.8 mg, 0.28 mmol, 94%); mp 111 °C.
IR (neat): 3047, 2962, 2910, 1660, 1592, 1421, 1313, 1137, 819,
694 cm–1.
1H NMR: δ = 7.42–7.35 (m, 2 H), 7.31 (dt, J = 8.4, 1.7 Hz, 2 H),
7.25–7.19 (m, 1 H), 6.70 (dt, J = 9.7, 4.2 Hz, 1 H), 6.08 (dt, J = 9.8,
1.8 Hz, 1 H), 3.85 (t, J = 6.9 Hz, 2 H), 2.59–2.44 (m, 2 H).
13C NMR: δ = 164.1 (C), 142.9 (C), 140.3 (CH), 129.0 (2 CH),
126.3 (CH), 126.2 (CH), 125.2 (2 CH), 48.8 (CH2), 24.8 (CH2).
GC-MS (EI): m/z = 225, 196, 182, 170, 143, 128, 115, 102, 89, 77,
63, 55, 39, 27.
Anal. Calcd for C15H15NO (225.12): C, 79.97; H, 6.71; N, 6.22.
Found: C, 79.81; H, 6.45; N, 6.39.
1-[5-Vinyl-1H-benzo[c]azepin-2(3H)-yl]prop-2-en-1-one (29)
Substrate 29 was synthesized, following the RP4, from compound
12 (74 mg, 0.33 mmol) and was isolated (eluent for chromatogra-
phy: EtOAc–hexane, 1:1) as a yellow oil (55 mg, 0.24 mmol, 74%).
GC-MS (EI): m/z = 173, 144, 105, 77, 68, 51, 39, 27.
Anal. Calcd for C11H11NO (173.01): C, 76.28; H, 6.40; N, 8.09.
Found: C, 76.31; H, 6.44; N, 8.04.
IR (neat): 3473, 3026, 2919, 2861, 1645, 1610, 1431, 1215, 979,
774 cm–1.
1H NMR: δ = 7.50–7.29 (m, 4 H), 6.73–6.49 (m, 2 H), 6.32–6.29 (m,
1 H), 6.12 (dt, J = 18.1, 7.0 Hz, 1 H), 5.75–5.66 (m, 1 H), 5.38–5.24
(m, 2 H), 4.51 (s, 1 H), 4.41 (s, 1 H), 3.97 (d, J = 6.9 Hz, 1 H), 3.81
(d, J = 7.2 Hz, 1 H).
13C NMR: δ = 165.2 (C, IA), 165.0 (C, IB), 144.9 (C, IA), 143.8 (C,
IB), 137.3 (CH, IA), 137.2 (C, IA), 137.0 (C, IB), 136.9 (CH, IB),
135.9 (C, IA), 135.5 (C, IB), 130.5 (CH, IA), 129.3 (CH, IA), 128.9
(CH, IB), 128.5 (CH, IB), 128.3 (2 CH, IA and CH, IB), 128.0 (CH,
IA), 127.9 (CH, IB), 127.8 (CH2, IA), 127.7(CH2, IB), 127.6 (CH, IB),
125.1 (CH, IA), 123.6 (CH, IB), 118.2 (CH2, IA), 117.5 (CH2, IB),
50.1 (CH2, IA), 47.2 (CH2, IB), 43.6 (CH2, IA), 41.3 (CH2, IB). IA and
IB refer to the major and minor rotamer, respectively.
1-(2-Iodobenzoyl)-1H-pyrrol-2(5H)-one (36)
Substrate 36 was synthesized, following the RP4, from compound
19 (102.3 mg, 0.3 mmol) and was isolated (eluent for chromatogra-
phy: EtOAc–hexane, 1:1) as a brown oil (94 mg, 0.3 mmol, quant).
IR (neat): 3463, 3057, 2924, 1734, 1678, 138, 1211, 805, 622 cm–1.
1H NMR: δ = 7.82 (d, J = 7.9 Hz, 1 H), 7.44–7.37 (m, 2 H), 7.25–
7.23 (m, 1 H), 7.14 (td, J = 7.8, 1.6 Hz, 1 H), 6.11 (dt, J = 6.0, 1.8
Hz, 1 H), 4.59 (t, J = 1.9 Hz, 2 H).
13C NMR: δ = 168.5 (C), 168.3(C), 147.5 (CH), 141.8 (C), 138.8
(CH), 130.9 (CH), 128.1 (CH), 127.3 (CH, 127.2 (CH), 91.6 (C),
50.5 (CH2).
GC-MS (EI): m/z = 314, 256, 231, 203, 186, 158, 130, 76, 50, 39.
Anal. Calcd for C11H8INO2 (313.09): C, 42.20; H, 2.58; N, 4.47.
Found: C, 42.27; H, 2.49; N, 4.52.
GC-MS (EI): m/z = 225, 196, 170, 155, 141, 128, 115, 102, 89, 63,
55, 39, 27.
(2,5-Dihydro-1H-pyrrol-1-yl)(2-ethynylphenyl)methanone (37)
Substrate 37 was synthesized, following the RP4, from compound
22 (67.5 mg, 0.3 mmol) and was isolated (eluent for chromatogra-
phy: EtOAc–hexane, 3:7) as a yellow oil (29 mg, 0.15 mmol, 49%).
Anal. Calcd for C15H15NO (225.29): C, 79.97; H, 6.71; N, 6.22.
Found: C, 80.05; H, 6.82; N, 6.16.
1-Benzyl-1H-pyrrol-2(5H)-one (33b)
IR (neat): 2992, 2938, 2863, 1678, 1615, 1421, 1215, 1115, 912,
821, 709 cm–1.
1H NMR: δ = 7.51–7.27 (m, 4 H), 5.99–5.77 (m, 1 H), 5.62–5.45 (m,
Substrate 33b was synthesized, following the RP4, from compound
11b (60.3 mg, 0.3 mmol) and was isolated (filtration through a short
pad of silica gel as a brown oil (50.9 mg, 0.29 mmol, 98%).
IR (neat): 3085, 3028, 2918, 1700, 1451, 1244, 732, 698 cm–1.
1 H), 4.43 (br, 1 H), 4.13 (br, 1 H), 3.15–3.01 (m, 3 H).
13C NMR: δ = 169.9 (C), 140.4 (C), 132.2 (CH), 131.2 (CH), 131.1
(CH), 129.9 (C), 128.7 (CH), 128.2 (CH), 127.9 (CH), 80.5 (C),
79.3 (CH), 55.1 (CH2), 54.9 (CH2).
1H NMR: δ = 7.41–7.14 (m, 5 H), 7.03 (dt, J = 6.0, 1.7 Hz, 1 H),
6.20 (dt, J = 6.0, 1.8 Hz, 1 H), 4.62 (s, 2 H), 3.85 (t, J = 1.7 Hz, 2 H).
13C NMR: δ = 171.4 (C), 142.9 (CH), 137.3 (C) 128.8 (2 CH), 127.9
GC-MS (EI): m/z 197, 177, 143, 119, 95, 55, 42, 28.
(3 CH), 127.6 (CH), 52.3 (CH2), 45.9 (CH2).
Anal. Calcd for C13H11NO (197.24): C, 79.17; H, 5.62; N, 7.10.
Found: C, 79.28; H, 5.66; N, 7.05.
GC-MS (EI): m/z = 174, 144, 115, 106, 91, 68, 51, 39, 28.
The spectral data of this compound correspond to the previously re-
ported data.19b
1-(2-Iodobenzyl)-5,6-dihydropyridin-2(1H)-one (38)
Substrate 38 was synthesized, following the RP4, from compound
24 (102.3 mg, 0.3 mmol) and was isolated (filtration through a short
pad of silica gel) as a brown solid (71.4 mg, 0.23 mmol, 76%); mp
82 °C.
1-(4-Iodophenyl)-1H-pyrrol-2(5H)-one (34b)
Substrate 34b was synthesized, following the RP4, from compound
14b (93.9 mg, 0.3 mmol) and was isolated (eluent for chromatogra-
phy: EtOAc–hexane, 1:1) as a brown solid (77.8 mg, 0.27 mmol,
91%); mp 105 °C.
IR (neat): 3463, 3053, 2938, 2893, 1665, 1608, 1483, 1436, 1292,
1013, 819, 748 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3523–3533

3532
E. Benedetti et al.
PAPER
A.; Zarantonello, P.; Seneci, P. J. Comb. Chem. 2001, 3,
1H NMR: δ = 7.81 (d, J = 7.9 Hz, 1 H), 7.30 (t, J = 7.5 Hz, 1 H), 7.24
(t, J = 7.7 Hz, 1 H), 6.94 (dd, J = 10.7, 4.3 Hz, 1 H), 6.63–6.55 (m,
1 H), 6.00 (d, J = 9.8 Hz, 1 H), 4.66 (s, 2 H), 3.35 (t, J = 7.1 Hz, 2
H), 2.44–2.29 (m, 2 H).
13C NMR: δ = 164.7 (C), 139.9 (CH), 139.6 (CH), 139.2 (C), 129.1
(CH), 128.6 (CH), 128.4 (CH), 125.3 (CH), 98.9 (C), 54.6 (CH2),
45.1 (CH2), 24.3 (CH2).
224. For more recent reports, see: (i) Seifert, J.; Pezeshki, S.;
Kamal, A.; Weisz, K. Org. Biomol. Chem. 2012, 10, 6850.
(j) Maggio, B.; Raffa, D.; Raimondi, M. V.; Plescia, F.;
Trincavelli, M. L.; Martini, C.; Meneghetti, F.; Basile, L.;
Guccione, S.; Daidone, G. Eur. J. Med. Chem. 2012, 54, 709.
(k) Moran, M. D.; Wilson, A. A.; Elmore, C. S.; Parkes, J.;
Ng, A.; Sadovski, O.; Graff, A.; Daskalakis, Z. J.; Houle, S.;
Chapdelaine, M. J.; Vasdev, N. Bioorg. Med. Chem. 2012,
20, 4482. (l) Gunawan, S.; Ayaz, M.; De Moliner, F.; Frett,
B.; Kaiser, C.; Patrick, N.; Xu, Z.; Hulme, C. Tetrahedron
2012, 68, 5606. (m) Ding, Z.-Y.; Chen, F.; Qin, J.; He, Y.-
M.; Fan, Q.-H. Angew. Chem. Int. Ed. 2012, 51, 5706.
(n) Parmar, N. J.; Barad, H. A.; Pansuriya, B. R.; Teraiya, S.
B.; Gupta, V. K.; Kant, R. Bioorg. Med. Chem. Lett. 2012,
22, 3816. (o) Qian, J.; Liu, Y.; Cui, J.; Xu, Z. J. Org. Chem.
2012, 77, 4484. (p) Das, A. N.; Chattopadhyay, P. J. Org.
Chem. 2012, 77, 5399. (q) Faigl, F.; Mátravölgyi, B.; Deák,
S.; Holczbauer, T.; Czugler, M.; Balázs, L.; Hermecz, I.
Tetrahedron 2012, 68, 4259. (r) Ichikawa, M.; Ohtsuka, M.;
Ohki, H.; Haginoya, N.; Itoh, M.; Sugita, K.; Usui, H.;
Suzuki, M.; Terayama, K.; Kanda, A. Bioorg. Med. Chem.
2012, 20, 3072. (s) Liégeois, J.-F.; Deville, M.; Dilly, S.;
Lamy, C.; Mangin, F.; Résimont, M.; Tarazi, F. I. J. Med.
Chem. 2012, 55, 1572. (t) Seto, S.; Yumoto, K.; Okada, K.;
Asahina, Y.; Iwane, A.; Iwago, M.; Terasawa, R.; Shreder,
K. R.; Murakami, K.; Kohno, Y. Bioorg. Med. Chem. 2012,
20, 1188. (u) Das, A. N.; Chattopadhyay, P. Eur. J. Org.
Chem. 2011, 36, 7346. (v) Balthaser, B. R.; Maloney, M. C.;
Beeler, A. B.; Porco, J. A. Jr.; Snyder, J. K. Nat. Chem. 2011,
3, 969. (w) Fujimoto, T.; Kunitomo, J.; Tomata, Y.; Marui,
S.; Nishiyama, K.; Nakashima, M.; Yoshikubo, S.-I.; Hirai,
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(x) Ogawa, T.; Kumagai, N.; Shibasaki, M. Angew. Chem.
Int. Ed. 2012, 51, 8551. (y) Fodor, L.; Csomós, P.; Csámpai,
A.; Sohár, P. Tetrahedron 2012, 68, 6581.
GC-MS (EI): m/z = 314, 217, 186, 157, 118, 107, 91, 63, 53.
Anal. Calcd for C12H12INO (313.13): C, 46.03; H, 3.86; N, 4.47.
Found: C, 46.21; H, 3.59; N, 4.34.
1-(6-Vinyl-3,4-dihydrobenzo[c]azocin-2(1H)-yl)prop-2-en-1-
one (39)
Substrate 39 was synthesized, following the RP4, from compound
25 (71.7 mg, 0.3 mmol) and was isolated (eluent for chromatogra-
phy: EtOAc–hexane, 1:1) as a yellow oil (49.5 mg, 0.21 mmol,
69%).
IR (neat): 3454, 2933, 2852, 1664, 1610, 1483, 1293, 1141, 908,
820, 769 cm–1.
1H NMR: δ = 7.36–7.18 (m, 3 H), 7.16–7.05 (m, 1 H), 6.63 (dd, J =
17.3, 10.4 Hz, 1 H), 6.57–6.49 (m, 1 H), 6.00 (dt, J = 9.8, 1.7 Hz, 1
H), 5.48–5.37 (m, 1 H), 5.16 (d, J = 10.4 Hz, 1 H), 5.09 (s, 1 H),
4.72 (d, J = 17.3 Hz, 1 H), 4.56 (s, 2 H), 3.21 (t, J = 7.2 Hz, 2 H),
2.34–2.22 (m, 2 H).
13C NMR: δ = 164.9 (C), 147.4 (2 C), 139.51 (CH), 139.2 (CH),
135.2 (C), 129.9 (CH), 127.9 (CH), 127.5 (C), 127.1 (CH), 125.5
(CH), 119.2 (CH2), 117.7 (CH2), 46.8 (CH2), 44.5 (CH2), 24.3
(CH2).
GC-MS (EI): m/z = 238, 170, 142, 128, 115, 98, 53, 42.
Anal. Calcd for C16H17NO (239.13): C, 80.30; H, 7.16; N, 5.85.
Found: C, 80.52; H, 7.01; N, 5.67.
Acknowledgment
(3) (a) Kondo, K.; Ogawa, H.; Yamashita, H.; Miyamoto, H.;
Tanaka, M.; Nakaya, K.; Kitano, K.; Yamamura, Y.;
Nakamura, S.; Onogawa, T.; Mori, T.; Tominaga, M.
Bioorg. Med. Chem. 1999, 7, 1743. (b) Ogawa, H.;
The authors would like to thank Dr. Enrica Alberti for NMR expe-
riments, and Giuditta Perazzoli and Alessandro Frigerio for experi-
mental assistance. The present work was supported by Ministero
dell’Istruzione, dell’Universita e della Ricerca (PRIN 2008). Pro-
grammi di Ricerca Scientifica di Rilevante Interesse Nazionale (Ot-
timizzazione della sintesi di molecole eterocicliche e carbocicliche
mediante l’uso di procedure non convenzionali-‘Approccio eco-
compatibile all’intensificazione di processo nella sintesi organica’
prot. 2008M3Y5WX).
Yamashita, H.; Kondo, K.; Yamamura, Y.; Miyamoto, H.;
Kan, K.; Kitano, K.; Tanaka, M.; Nakaya, K.; Nakamura, S.;
Mori, T.; Tominaga, M.; Yabuuchi, Y. J. Med. Chem. 1996,
39, 3547. (c) Tahara, A.; Tsukada, J.; Tomura, Y.; Momose,
K.; Suzuki, T.; Yatsu, T.; Shibasaki, M. Eur. J. Pharmacol.
2006, 538, 32. (d) Sum, F.; Dusza, J.; Delos Santos, E.;
Grosu, G.; Reich, M.; Du, X.; Albright, J. D.; Chan, P.;
Coupet, J.; Ru, X.; Mazandarani, H.; Saunders, T. Bioorg.
Med. Chem. Lett. 2003, 13, 2195. (e) Kunick, C.; Bleeker,
C.; Prühs, C.; Totzke, F.; Schächtele, C.; Kubbutat, M. H.
G.; Link, A. Bioorg. Med. Chem. Lett. 2006, 16, 2148.
(f) Zhao, H.; Zhang, X.; Hodgetts, K.; Thurkauf, A.;
Hammer, J.; Chandrasekhar, J.; Kieltyka, A.; Brodbeck, R.;
Rachwal, S.; Primus, R.; Manly, C. Bioorg. Med. Chem.
Lett. 2003, 13, 701. (g) Floyd, D.; Kimball, D.; Krapcho, J.;
Das, J.; Turk, C. F.; Moquin, R. V.; Lago, M. W.; Duff, K.
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Brittain, R. J.; Normandin, D. E.; Hedberg, A.; Cucinotta, G.
J. Med. Chem. 1992, 35, 756. (h) Donati, D.; Di Fabio, R.
Pharm. Acta Helv. 2000, 74, 239. (i) Zuccotto, F.; Zvelebil,
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Maes, L.; Ruiz-Perez, L. M.; Pacanowska, D.; Gilbert, I. H.
G. Eur. J. Med. Chem. 2001, 36, 395.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. SunpIgpfoi
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3523–3533