Sequential ring-closing metathesis-vinyl halide Heck cyclization reactions: Access to the tetracyclic ring system of ervitsine

Article abstract of DOI:10.1016/j.tet.2012.04.022

A chemoselective indole-templated ring-closing metathesis is used to assemble the cyclohepta[b]indole substructure of the indole alkaloid ervitsine. A subsequent intramolecular Heck coupling of the resulting alkene functionality with an amino-tethered vinyl halide accomplishes the closure of the unique 2-azabicyclo[4.3.1]decane framework of the alkaloid with concomitant incorporation of the exocyclic E-ethylidene substituent.

Full text of DOI:10.1016/j.tet.2012.04.022

Tetrahedron 68 (2012) 4641e4648
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Sequential ring-closing metathesisevinyl halide Heck cyclization reactions: access
to the tetracyclic ring system of ervitsine
*
ꢀ
M.-Lluïsa Bennasar , Ester Zulaica, Daniel Sole, Sandra Alonso
Laboratory of Organic Chemistry, Faculty of Pharmacy, and Institut de Biomedicina (IBUB), University of Barcelona, Barcelona 08028, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 March 2012
Received in revised form 29 March 2012
Accepted 4 April 2012
Available online 19 April 2012
A chemoselective indole-templated ring-closing metathesis is used to assemble the cyclohepta[b]indole
substructure of the indole alkaloid ervitsine. A subsequent intramolecular Heck coupling of the resulting
alkene functionality with an amino-tethered vinyl halide accomplishes the closure of the unique 2-
azabicyclo[4.3.1]decane framework of the alkaloid with concomitant incorporation of the exocyclic E-
ethylidene substituent.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Alkaloids
Ervitsine
Ring-closing metathesis
Heck cyclization
1. Introduction
approach to the bridged ervitsine framework relying on an indole-
templated ring-closing metathesis (RCM)6 to first construct the
Ervitsine1 is a minor indole alkaloid isolated in 1977 from Pan-
daca boiteaui (Apocynaceae)2 with an unique tetracyclic framework
comprising a 2-azabicyclo[4.3.1]decane system fused to the indole
ring and two exocyclic alkylidene (16-methylene and 20E-ethyl-
idene) substituents. This complex architecture attracted the syn-
thetic interest of research groups in the eighties and early nineties,
resulting in a few approaches to the core structure3,4 and a total
synthesis based on biomimetic considerations.5 Despite the variety
of strategies used, all routes have in common the formation of the
central carbocyclic ring in the last synthetic steps, either by cycli-
zation of an iminium-type ion upon the indole 3-position (bond
formed C5eC7, a)3a,d,4,5 or by FriedeleCrafts acylation of the indole
2-position (bond formed C2eC3, b).3b,c,e
central seven-membered ring and a vinyl halide Heck cyclization7
to close the piperidine ring and at the same time install the req-
uisite 20E-ethylidene substituent (bond formed C15eC20, c).8 As
shown in Scheme 1, the metathetic ring closure of 2,3-
dialkenylindoles of general structure A would provide cyclohepta
[b]indoles B, with the appropriate double bond functionality for the
subsequent intramolecular Heck reaction with the amino-tethered
vinyl halide.9 It should be noted that similar Heck couplings of vinyl
halides and elaborated cyclohexenes10 or cycloheptenes11 have
proved to be useful for the assembly of the bridged core of several
indole alkaloids. In this context, we have successfully explored vinyl
halide Heck reactions upon azocine and azonine rings for the total
synthesis of apparicine12 and cleavamines.13
20
MeN16
2. Results and discussion
c
H
5
H
a
15
7
a refs 3a, 3d, 4,5
To explore the feasibility of the double annulation RCMeHeck
methodology for the ervitsine construction, we initially focused on
indolic precursors unfunctionalized at the benzylic
3
2
b refs 3b, 3c, 3e
c this work
N
H
b
O
a-position
(Scheme 1, Y¼H, H), knowing that this methylene group could be
oxidized at a later stage of the synthesis.14 Thus, cyclohepta[b]in-
doles 7e9 and 13 were selected as substrates for the key Heck re-
action bearing different (carbamate, amine, and amide) exocyclic
nitrogen atoms (Scheme 2). The synthetic route began with 2-allyl-
3-indolecarbaldehyde 1,15 which was equipped with a strong
electron-withdrawing group at the nitrogen to guarantee the sta-
bility of the gramine [3-(aminomethyl)indole] moiety of the
Ervitsine
(biogenetic numbering)
Our long-standing interest in the development of indole annu-
lation methodologies led us to envisage a straightforward synthetic
* Corresponding author. Tel./fax: þ34 934024540; e-mail address: bennasar@
ub.edu (M.-L. Bennasar).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.022

4642
M.-L. Bennasar et al. / Tetrahedron 68 (2012) 4641e4648
cycloheptenes 7, 8, and 13 as the only products in 80%, 78%, and 87%
X
X
R2
R1
R1
R1
20
15
yield, respectively. The tertiary amine 6 was a worse RCM substrate,
requiring the previous conversion into the corresponding hydro-
chloride to afford 9 in a slightly lower yield (65%).
N
N
N
N
Z
RCM
Heck
We also sought to elaborate functionalized tricyclic ervitsine
substructures (B, Y¼H, OH or O, Scheme 1) but all our efforts met
with failure. The simple extension of the chemistry outlined above
to an O-protected 2-(1-hydroxyallyl)indole such as 1515 (Scheme 3)
proved impractical as the formyl group required for the amina-
tioneimine allylation step could not be introduced, only
complex mixtures being obtained when 14 was subjected to the
FriedeleCrafts protocol (Cl2CHOMe, TiCl4).
Y
N
Y
N
Y
PG
PG
PG
R1 = Me, CO2Me
B
A
R2 = protecting group
Z = Br, I
X, Y = H,H; H,OH; O
X
or
Z
Scheme 1. Synthetic plan.
I
MeO2C
CHO
N
intermediates. From this compound, an aminationeimine allylation
sequence was devised to install the homoallylic amine moiety re-
quired for the RCM step. We chose a direct route without using
protecting groups and incorporated the additional haloalkenyl
appendage either at the amination step (for 7e9) or at the final
acylation step (for 13), with the hope that it would be sufficiently
inert under the RCM conditions. Reaction of aldehyde 1 with (Z)-2-
bromo-2-butenylamine (2a), followed by alkylation of the resulting
imine with allylmagnesium bromide led to the unstable secondary
amine 3a (not isolated), which was subsequently acylated with
ClCO2Me or alkylated with formaldehyde and NaCNBH3 to give
carbamate 4 or tertiary amine 6 in 60% and 50% overall yield, re-
spectively. Starting from 1 and (Z)-2-iodo-2-butenylamine (2b),
carbamate 5 was similarly prepared in 65% overall yield through
secondary amine 3b. On the other hand, reaction of aldehyde 1 with
methylamine and allylation of the resulting imine as above gave the
unstable secondary amine 10, which was converted into amide 12
in 60% overall yield by acylation with (Z)-2-bromo-2-butenoic acid
(11) in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbo-
diimide (EDC).
N
N
OTBDMS
OTBDMS
SO2Ph
SO2Ph
N
O
SO2Ph
14
15
Scheme 3.
We then planned to install the homoallylic amine moiety on an
indole-3-carbaldehyde such as 1616 or 1717 before functionalizing
the 2-position either by direct metalation or metalehalogen ex-
change followed by electrophilic trapping (Scheme 4). Given that
the base-sensitive halovinyl chain would probably be incompatible
with the latter reaction, it would be introduced after the RCM step.
Aldehyde 16 was uneventfully converted into carbamate 18 by
successive treatment with methylamine, allylmagnesium bromide,
and di-tert-butyl dicarbonate, but treatment of this substrate with
LDA or alkyl lithium derivatives (s-BuLi, t-BuLi) in THF under a va-
riety of experimental conditions, followed by addition of DMF,
HCO2Me, or acrolein, only led to the recovery of the starting ma-
terial. More satisfactorily, the desired functionalization took place
by lithiumehalogen exchange from carbamate 19, which was pre-
pared as above from aldehyde 17. Treatment with t-BuLi in THF at
ꢀ78ꢁ C followed by quenching with acrolein led to an unstable
alcohol, which was immediately oxidized with MnO2 to give ketone
20 in 45% overall yield. Unfortunately, while RCM of 20 took place in
the presence of the second generation Grubbs catalyst in refluxing
CH2Cl2 to give the expected cyclopentenone 21 in 65% yield (not
optimized), all attempts to remove the Boc protecting group for the
At this point we proceeded to study the RCM reaction. Consid-
ering the different substitution and electronic nature of the double
bonds of the trienic substrates, we expected the preferred RCM
event to be the indole-templated cyclization leading to a fused
seven-membered ring. Our expectations were confirmed when
carbamates 4 and 5 as well as amide 12, on exposure to the second
generation Grubbs catalyst in refluxing CH2Cl2, gave the desired
Z
R1
Z
R1
Z
N
H2N
1.
CHO
HN
N
Grubbs II
2nd gen.
Z
3. ClCO2Me
or
(2)
2. BrMgCH2CH=CH2
N
CH2Cl2
reflux
N
HCHO, NaCNBH3
SO2Ph
N
N
SO2Ph
a Z = Br
b Z = I
SO2Ph
1
SO2Ph
3
4 (60%) R1 = CO2Me, Z = Br 7 (80%)
5 (65%) R1 = CO2Me, Z = I
6 (50%) R1 = Me, Z = Br
8 (78%)
9 (65%)
1. NH2CH3
2. BrMgCH2CH=CH2
O
N
O
N
Br
H
N
Br
Me
O
Me
Me
Grubbs II
nd gen.
HO
2
(11)
Br
N
N
N
EDC
60%
CH2Cl2
reflux
SO2Ph
SO2Ph
SO2Ph
87%
13
10
12
Scheme 2. Synthesis of cyclohepta[b]indoles 7e9 and 13.

M.-L. Bennasar et al. / Tetrahedron 68 (2012) 4641e4648
4643
subsequent derivatization of the secondary amine invariably led to
tropone 22.
starting product being invariably recovered even under longer re-
action times.
It should be mentioned that the analogous N-methyl derivative
9 (Scheme 5) led to complex reaction mixtures under any of the
above Heck conditions. This result seemed to indicate that the
presence of a basic nitrogen in the halobutene chain is not com-
patible with the harsh cyclization conditions, probably due to
a competitive dealkylation process. So, unsurprisingly, amide 13
proved to be a more robust substrate leading to tetracyclic lactam
25 in 50% yield.
Boc
Me
N
CHO
1. MeNH2
2. BrMgCH2CH=CH2
(from 19)
1. t-BuLi
R
R
N
3. (t-BuOCO)2O
2. acroleine
3. MnO2
N
MOM
MOM
16 R = H
17 R = Cl
18 R = H (80%)
45%
19 R = Cl (85%)
Boc
Boc
Me
Me
N
Me
N
Br
N
Me
Grubbs II
N
2nd gen.
H
see
text
Pd(0)
H
CH2Cl2
reflux
65%
N
O
N
O
N
MOM
O
N
MOM
MOM
(see text)
N
SO2Ph
20
22
21
SO2Ph
Scheme 4.
9
O
N
O
We turned our attention to the intramolecular Heck coupling to
complete the bridged framework of ervitsine. Table 1 summarizes
the survey of experimental conditions, including palladium pre-
catalysts, ligands, and additives, using carbamates 7 and 8 as sub-
strates. As can be observed in entry 1, only the starting product was
recovered when vinyl bromide 7 was subjected to classical polar
conditions10a (Pd(OAc)2, PPh3, Et3N, CH3CN). On the other hand, the
use of ligand-free conditions introduced by Jeffery18 (Pd(OAc)2,
K2CO3, TBACl, DMF, entry 2), which had proven successful for the
synthesis of related azapolycyclic structures,10b,c,e resulted in the
total decomposition of the material. More successfully, the desired
cyclization proceeded upon treatment of 7 under non-polar con-
ditions11 (palladium catalyst, PPh3, proton sponge, K2CO3, toluene,
entries 3 and 4). However, although the conversion yields were
good as evidenced by the NMR analysis of the crude reaction
mixtures, the isolated yields of the (E)-ethylidene tetracycle 23
after column chromatography were only moderate (30%), the
H3C
H
Br
Me
N
Pd(OAc)2, Ph3P
Proton Sponge
H
toluene, reflux, 24 h
50%
N
N
SO2Ph
SO2Ph
13
25
Scheme 5. Heck cyclization of 9 and 13.
We then focused on the more reactive vinyl iodide 8. When
subjected to the same non-polar protocol (entry 5), tetracycle 23
was obtained only in a slightly better yield (45%) along with minor
amounts of recovered starting product. To increase the efficiency
of the process we examined the reaction in the presence of other
additives, such as phenol or Ag2CO3. We were pleased to find that
the addition of 20 mol % phenol in combination with K3PO4
Table 1
Heck cyclization of cyclohepta[b]indoles 7 and 8
MeO2C
MeO2C
N
Z
N
MeO2C
N
H
H
H
Pd(0)
H
N
N
N
SO2Ph
SO2Ph
SO2Ph
24
23
7
8
Z = Br
Z = I
Entry
Substrate
Reaction conditions
Products (yield %)a
1
2
3
7
7
7
Pd(OAc)2 (16%), PPh3 (50%), Et3N (2 equiv), CH3CN, reflux, 3 h
7 (33)
ee
Pd(OAc)2 (5%), K2CO3 (5 equiv), TBACl (1 equiv), DMF, 60 ꢁC, 4 h
Pd(OAc)2 (5%), PPh3 (20%), proton sponge (0.5 equiv), K2CO3 (1.1 equiv), toluene, reflux, 4 h
Pd(PPh3)4 (5%), proton sponge (0.1 equiv), K2CO3 (2.5 equiv), toluene, sealed tube, 2.5 days
Pd(OAc)2 (10%), PPh3 (40%), proton sponge (0.3 equiv), K2CO3 (1.5 equiv), toluene, reflux, 24 h
23 (30)
7 (16)
23 (30)
7 (5)
23 (45)
8 (10)
23 (65)
23 (45)
24 (15)
23 (19)
24 (43)
23 (25)
24 (25)
4
5
7
8
6
7
8
8
Pd(PPh3)4 (10%), K3PO4 (3 equiv), Et3N (6 equiv), phenol (0.2 equiv), toluene, reflux, 12 h
Pd(OAc)2 (10%), PPh3 (30%), Ag2CO3 (3 equiv), toluene, reflux, 40 min
8
9
8
8
Pd(OAc)2 (10%), PPh3 (30%), Ag2CO3 (3 equiv), toluene, 80 ꢁC, 1 h
Pd(OAc)2 (10%), dppe (12%), Ag2CO3 (3 equiv), DIPEA (2 equiv), toluene, reflux, 2 h
a
Isolated yields after column chromatography.

4644
M.-L. Bennasar et al. / Tetrahedron 68 (2012) 4641e4648
resulted in a cleaner cyclization, giving the ervitsine tetracycle 23
as the only product in 65% yield (entry 6). As far as we know, the
use of phenol as a catalytic additive in the Heck reaction is un-
precedented, although its positive role in some palladium-
catalyzed arylations of ketone enolates has been previously ob-
served.19,20 According to these reports,19 the intermediacy of
a palladium phenoxide (e.g., C), which would stabilize an other-
wise unstable intermediate, could account for the beneficial effect
of the added phenol.
3. Conclusions
We have succeeded in synthesizing tetracycles 23 and 25, which
embody the 4E-ethylidene-2-azabicyclo[4.3.1]decane bridged core
of the indole alkaloid ervitsine, using a combination of an indole-
templated RCM and a vinyl halide Heck cyclization. This result
highlights the power of the double annulation RCMeHeck meth-
odology for rapidly building up the highly complex structure
present in some indole alkaloids.
MeO2C
N
L
4. Experimental section
4.1. General
Pd
O
N
C
All nonaqueous reactions were carried out under an argon at-
mosphere. All solvents were dried by standard methods. Reaction
courses and product mixtures were routinely monitored by TLC on
SiO2 (silica gel 60 F254) and the spots were located with aqueous
potassium permanganate solution. Drying of organic extracts was
carried out over anhydrous Na2SO4. The solvents were evaporated
under reduced pressure with a rotary evaporator. Column chro-
matography was carried out using the flash chromatography
technique on SiO2 (silica gel 60, SDS, 0.04e0.06 mm). NMR spectra
were recorded in CDCl3 using Me4Si as an internal reference. HRMS
were obtained using an LC/MSD TOF mass spectrometer.
SO2Ph
On the other hand, although the starting material was rapidly
consumed in the presence of Ag2CO3 (entries 7e9), the cyclization
followed a different course as it led to mixtures of tetracycles 23
and 24, the latter coming from an apparent 7-endo cyclization with
inversion of the ethylidene configuration.21 Tetracycle 23 was the
major product when the reaction was carried out in refluxing tol-
uene (entry 7) while the formation of the abnormal product 24 was
enhanced by working at lower temperatures (entry 8) or changing
the ligand from Ph3P to dppe (entry 9).
The formation of unusual Heck cyclization products like 24
has been previously observed12b,22 and rationalized23 by con-
sidering that the initial 6-exo cyclization is not followed by the
4.2. Synthesis of the RCM substrates
4.2.1. (Z)-2-Bromo-2-butenylamine (2a). (Z)-1,2-dibromo-2-butene25
(3.12 g, 14.6 mmol) was added dropwise (1 h) to a solution of hexa-
methylenetetramine (2.25 g, 16 mmol) in CHCl3 (18 mL) heated at
reflux. The resulting mixture was heated at reflux for 4 h and then
allowed to stand in the refrigerator overnight. The mixture was
cooled in an ice bath and the quaternary salt was collected by fil-
tration. The crude salt was dissolved in a warm solution, prepared
from H2O (6 mL), EtOH (29 mL), and 37% HCl (8 mL). The mixture was
stirred for 4 h and then allowed to stand overnight. A precipitate of
NH4Cl was formed, which was removed by filtration, washing care-
fully with ethanol. The filtrate was concentrated to a quarter of the
volume and the resulting solid was removed by filtration. The filtrate
was concentrated to dryness and the solid residue was carefully
dried. The residue was digested with MeOH (15 mL) and the resulting
solid was removed by filtration. The filtrate was concentrated to
dryness to give 2a hydrochloride (2.75 g, quantitative), which was
used in the next reaction without purification.
expected b-hydride elimination (which would lead to 23) but by
an intramolecular carbopalladation on the exocyclic alkene. The
resulting cyclopropane intermediate would undergo rearrange-
ment, with concomitant inversion of the alkene geometry, and
final b-hydride elimination. In our case, the competitive forma-
tion of 24 is only observed in the presence of Ag2CO3, probably
because under these cationic conditions the benzenesulfonyl
group is able to weakly coordinate with the initially formed
cationic
s
-alkyl palladium intermediate to give
a seven-
membered palladacycle24 (Scheme 6). The
b
-hydride elimina-
tion would thus be partially prevented and the intramolecular
cyclopropanation route favored, in particular when the reaction
is performed at a relatively low temperature or in the presence of
a chelating phosphine such as dppe.
MeO2C
N
L
-hydride
Pd
23
4.2.2. 2-Allyl-3-[1-[N-(Z)-(2-bromo-2-butenyl)-N-(methoxycarbonyl)-
amino]-3-butenyl]-1-(phenylsulfonyl)indole (4). Et3N (0.31 mL, 2.23 -
mmol) was added to a solution of amine 2a hydrochloride (0.29 g,
1.5 mmol) in CH2Cl2 (5 mL) and the mixture was stirred at rt for
10 min. Aldehyde 115 (0.34 g, 1.0 mmol) in CH2Cl2 (5 mL) and AcOH
(0.06 mL, 1.0 mmol) were successively added and the resulting
mixture was stirred at rt for 18 h. The reaction mixture was diluted
with CH2Cl2 (5 mL), basified with a saturated aqueous Na2CO3 solu-
tion (10 mL), and extracted with CH2Cl2 (2ꢂ10 mL). The organic ex-
tracts were dried and concentrated to give the crude imine (480 mg).
Allylmagnesium bromide (1 M in Et2O, 1.6 mL, 1.6 mmol) was added
under Ar to a cooled (ꢀ78 ꢁC) solution of the above imine in anhy-
drous THF (30 mL), and the resulting mixture was stirred at rt for 2 h.
The reaction mixture was quenched with a 10% aqueous NH4Cl so-
lution (5 mL) and extracted with Et2O (3ꢂ10 mL). The ethereal ex-
tracts were dried and concentrated to give the crude amine 3a
(342 mg). A solutionof the above amine 3a in anhydrous THF (12 mL)
was added underAr to a suspension of NaH (60%, 56 mg,1.4 mmol) in
THF (2 mL) cooled at ꢀ20 ꢁC, and the mixture was stirred at ꢀ20 ꢁC
for 20 min. A solution of ClCO2Me (0.16 mL, 2.1 mmol) in THF (1 mL)
H
elimination
L
N
O
S
O
Ph
Pd(0)
8
Ag2CO3
H
MeO2C
MeO2C
N
N
Me
PdL2
H
cyclopropanation
L
Pd
L
N
O
O
Ph
S
bond rotation
Me
MeO2C
MeO2C
-hydride
elimination
N
PdL2
N
rearrangement
PdL2
24
H
Scheme 6.

M.-L. Bennasar et al. / Tetrahedron 68 (2012) 4641e4648
4645
was then added and the mixture was stirred at rt overnight. The re-
action mixture was quenched with H2O (10 mL) and extracted with
Et2O (2ꢂ15 mL). The combined organic extracts were dried and
concentrated. The resulting residue was chromatographed (97:3
hexanes/AcOEt) to give bromo triene 4 as a light brown oil: (0.35 g,
anhydrous THF (30 mL), and the resulting mixture was stirred at rt
overnight. The reaction mixture was quenched with a 10% aqueous
NH4Cl solution (10 mL) and extracted with Et2O (3ꢂ15 mL). The
ethereal extracts were dried and concentrated to give the crude
amine 10 (0.5 g). Butenoic acid 1127 (0.49 g, 3 mmol) and 1-ethyl-3-
(3-dimethylaminopropyl)carbodiimide (EDC, 0.46 g, 3 mmol) were
added to a solution of the above amine 10 in CH2Cl2 (30 mL) and the
mixture was stirred at rt for 2.5 days. The reaction mixture was
diluted with CH2Cl2 (10 mL) and washed with 1.5 M aqueous HCl
(2ꢂ10 mL) and aqueous 10% NaOH (2ꢂ10 mL). The resulting organic
solution was dried and concentrated and the resulting residue was
chromatographed (95:5 hexanes/AcOEt) to give the title compound
60%);1HNMR(400 MHz)
d
1.40(d, J¼6.4 Hz,3H), 2.90(m,2H), 3.72(s,
3H), 3.89 (m, 2H), 3.96 (br s, 2H), 4.95 (m, 2H), 5.03 (m, 2H), 5.41 (q,
J¼6.4 Hz, 1H), 5.56 (m, 1H), 5.60 (m, 1H), 5.96 (m, 1H), 7.26 (m, 2H),
7.41 (m, 2H), 7.53 (m, 1H), 7.66 (d, J¼8.0 Hz, 1H), 7.73 (m, 2H), 8.21
(dm, J¼8.0 Hz,1H); 13C NMR (74.5 MHz)
d 16.1 (CH3), 30.2 (CH2), 36.9
(CH2), 51.4 (CH2), 52.9 (CH3), 53.2 (CH), 115.1 (CH), 116.3 (CH2), 117.5
(CH2), 118.8 (C), 120.1 (CH), 123.2 (CH), 123.6 (CH), 124.2 (CH), 124.3
(C), 126.4 (2CH), 129.2 (2CH), 129.4 (C), 133.7 (CH), 134.4 (CH), 134.8
(CH), 136.5 (C), 138.3 (C), 138.9 (C), 156.6 (CO); ESI-HRMS [MþH]þ
calcd for C27H30BrN2O4S 557.1110, found 557.1104.
12 as a pale yellow foam: 0.48 g (60%); 1H NMR (400 MHz)
d 1.90 (d,
J¼6.6 Hz, 3H), 2.77 (s, 3H, NCH3), 2.90 (m, 2H), 3.90 (m, 2H), 5.00
(m, 4H), 5.70 (m, 1H), 5.95 (m, 2H), 6.05 (q, J¼6.6 Hz, 1H), 7.20 (m,
2H), 7.38 (m, 2H), 7.50 (m,1H), 7.70 (m, 3H), 8.25 (d, J¼8 Hz,1H); 13C
4.2.3. 2-Allyl-3-[1-[N-(Z)-(2-iodo-2-butenyl)-N-(methoxycarbonyl)
amino]-3-butenyl]-1-(phenylsulfonyl)indole (5). Operating as above,
from aldehyde 115 (0.20 g, 0.6 mmol) and the amine 2b hydro-
chloride26 (0.25 g, 1.0 mmol), carbamate 5 was obtained as a light
NMR (74.5 MHz) d 16.3 (CH3), 30.1 (CH2), 34.9 (CH2), 32.3 (CH3),
50.2 (CH), 115.5 (CH), 116.2 (CH2), 117.6 (C), 117.7 (CH2), 120.1 (CH),
123.8 (CH), 124.2 (CH), 126.3 (2CH), 127.0 (C), 129.1 (2CH), 129.3
(CH), 133.7 (CH), 134.0 (CH), 135.1 (CH), 135.2 (C), 136.8 (C), 138.5
(C), 138.9 (C), 166.3 (CO); ESI-HRMS [MþH]þ calcd for
C26H28BrN2O3S 527.1004, found 527.0979.
brown oil: 0.24 g (65%); 1H NMR (400 MHz)
d
1.30 (d, J¼6.4 Hz, 3H),
2.82 (m, 2H), 3.63 (s, 3H), 3.81 (m, 2H), 3.90 and 3.95 (2d, J¼16 Hz,
2H), 4.82 (d, J¼10.4 Hz, 1H), 4.90 (br s, 1H), 4.95 (m, 2H), 5.18 (q,
J¼6.4 Hz, 1H), 5.47 (m, 2H), 5.90 (m, 1H), 7.16 (m, 2H), 7.30 (m, 2H),
7.42 (m, 1H), 7.58 (dm, J¼8 Hz, 1H), 7.65 (m, 2H), 8.12 (d, J¼7.8 Hz,
4.3. RCM reactions
1H); 13C NMR (400 MHz)
d
21.3 (CH3), 30.4 (CH2), 36.7 (CH), 52.9
4.3.1. 10-[N-((Z)-2-Bromo-2-butenyl)-N-(methoxycarbonyl)amino]-
(CH3), 53.2 (CH), 54.7 (CH2), 105.5 (C), 115.0 (CH), 116.3 (CH2), 117.6
(CH2), 118.7 (C), 120.2 (CH), 123.7 (CH), 124.2 (CH), 126.4 (2CH),
129.0 (CH),129.2 (2CH),129.3 (C),133.8 (CH), 134.4 (CH),134.9 (CH),
136.4 (C), 138.2 (C), 138.9 (C), 156.6 (CO).
5-(phenylsulfonyl)-9,10-dihydro-6H-cyclohepta[b]indole
(7). The
second generation Grubbs catalyst (7 mol %) was added under Ar to
a solution of carbamate 4 (100 mg, 0.18 mmol) in CH2Cl2 (2.5 mL)
and the resulting mixture was heated at reflux for 2.5 h. The reaction
mixture was concentrated and the residue was chromatographed
(96:4 hexanes/AcOEt) to give the title compound 7 as a yellow oil:
4.2.4. 2-Allyl-3-[1-[N-(Z)-(2-bromo-2-butenyl)-N-methylamino]-3-
butenyl]-1-(phenylsulfonyl)indole
(6). Aldehyde
115
(0.17 g,
76 mg (80%); 1H NMR (400 MHz)
d
1.49 (dm, J¼6.5 Hz, 3H), 2.55 (br,
0.5 mmol) was allowed to react with 2a hydrochloride and allyl-
magnesium bromide as described for the preparation of carbamate
4. The resulting crude amine 3a (170 mg) was dissolved in CH3CN
(1.5 mL) and the resulting solution was treated with 37% aqueous
formaldehyde (1.7 mmol) and NaBH3CN (34 mg, 0.55 mmol) for
45 min at rt. The acidic pH was maintained with regular addition of
AcOH. The reaction mixture was basified with 2 N NaOH (5 mL),
diluted with H2O (10 mL), and extracted with Et2O (3ꢂ10 mL). The
organic layer was washed with 2 N NaOH (2ꢂ10 mL), dried, and
concentrated. The resulting residue was chromatographed (90:10
hexanes/AcOEt) to give 6 as a light brown oil: 134 mg (50%); 1H
1H), 2.65 (br,1H), 3.40 (d, J¼16.8 Hz,1H), 3.78 (br s, 3H), 4.05 (m, 3H),
5.36 (q, J¼6.5 Hz, 1H), 5.75 (m, 1H), 5.88 (m, 1H), 5.95 (m, 1H), 7.26
(m, 3H), 7.43 (m, 2H), 7.53 (m, 1H), 7.70 (m, 2H), 8.23 (d, J¼8.0 Hz,
1H); 13C NMR (74.5 MHz)
d 16.3 (CH3), 25.5 (br, CH2), 30.4 (br, CH2),
51.4 (br, CH), 51.9 (br, CH2), 53.0 (br, CH3), 115.3 (CH), 118.7 (br, CH),
120.0 (C), 123.0 (br, CH), 124.1 (CH), 124.8 (CH), 124.9 (C), 125.0 (C),
126.1 (2CH), 128.9 (CH), 129.3 (2CH),130.3 (CH),133.8 (CH), 136.1 (C),
137.2 (br, C), 138.7 (C), 156.7 (br, CO); ESI-HRMS [MþNa]þ calcd for
C25H25BrN2NaO4S 551.0616, found 551.0591.
4.3.2. 10-[N-((Z)-2-Iodo-2-butenyl)-N-(methoxycarbonyl)amino]-5-
(phenylsulfonyl)-9,10-dihydro-6H-cyclohepta[b]indole
(8). Operating as above, from carbamate 5 (0.30 g, 0.5 mmol), the
title compound 8 was obtained as a yellow oil after column chro-
matography (96:4 hexanes/AcOEt): 0.22 g (78%); 1H NMR (400 MHz,
NMR (400 MHz)
d
1.71 (d, J¼6.4 Hz, 3H), 2.11 (s, 3H), 2.58 (m, 1H),
2.76 (m, 1H), 3.11 (br s, 2H), 3.54 (dd, J¼9.6 and 4.8 Hz, 1H), 3.82 (m,
2H), 4.63 (d, J¼9.6 Hz,1H), 4.72 (d, J¼18.4 Hz,1H), 5.07 (m, 2H), 5.20
(m, 1H), 5.86 (q, J¼6.4 Hz, 1H), 5.99 (m, 1H), 7.20 (m, 1H), 7.24 (m,
1H), 7.32 (m, 2H), 7.46 (m, 1H), 7.61 (m, 2H), 7.91 (d, J¼7.6 Hz, 1H),
major rotamer)
d
1.51 (d, J¼6.0 Hz, 3H), 2.59 (br, 1H), 2.74 (br, 1H),
8.17 (d, J¼8.4 Hz, 1H); 13C NMR (74.5 MHz)
d
16.6 (CH3), 30.6 (CH2),
3.49 (d, J¼16 Hz, 1H), 3.71 (d, J¼16 Hz, 1H), 3.78 (br s, 3H), 3.99 (m,
2H), 5.25 (q, J¼6 Hz,1H), 5.72 (m,1H), 5.86 (m,1H), 5.95 (m,1H), 7.22
(m, 1H), 7.29 (m, 2H), 7.44 (m, 2H), 7.54 (m, 1H), 7.71 (m, 2H), 8.23 (d,
37.0 (CH2), 39.6 (CH3), 61.7 (CH), 63.8 (CH2), 115.2 (CH), 116.4 (CH2),
116.7 (CH2), 121.7 (CH), 122.6 (C), 123.5 (CH), 124.4 (CH), 125.6 (CH),
126.2 (2CH), 126.8 (C), 128.9 (2CH), 129.4 (C), 133.4 (CH), 135.2 (CH),
135.3 (CH), 136.0 (C), 137.1 (C), 138.6 (C); ESI-HRMS [MþH]þ calcd
for C26H30BrN2O2S 513.1205, found 513.1200.
J¼8.4 Hz, 1H); 13C NMR (74.5 MHz)
d 21.6 (CH3), 25.6 (br, CH2), 30.9
(br, CH2), 52.4 (br, CH), 53.1 (br, CH3), 55.1 (br, CH2), 106.9 (br, C),
115.2 (CH), 118.6 (br, CH), 119.7 (br, C), 124.1 (CH), 124.8 (CH), 126.1
(2CH), 126.4 (C), 128.9 (CH), 129.0 (CH), 129.4 (2CH), 130.2 (CH);
133.9 (CH), 136.1 (C), 137.2 (br, C), 138.8 (C), 156.9 (CO); ESI-HRMS
[MþNa]þ calcd for C25H25IN2NaO4S 599.0472, found 599.0474.
4.2.5. 2-Allyl-3-[1-(Z)-(2-bromo-N-methyl-2-butenamido)-3-
butenyl]-1-(phenylsulfonyl)indole (12). Methylamine (8 M in EtOH,
1.9 mL, 15 mmol) and AcOH (0.09 mL, 1.5 mmol) were successively
added to a solution of aldehyde 1 (0.5 g, 1.5 mmol) in CH2Cl2
(15 mL). After being stirred at rt overnight, the reaction mixture
was diluted with CH2Cl2 (10 mL), basified with a saturated Na2CO3
solution and extracted with CH2Cl2 (3ꢂ10 mL). The organic extracts
were dried and concentrated to give the crude imine: 0.5 g. Allyl-
magnesium bromide (1 M in Et2O, 2.4 mL, 2.4 mmol) was added
under Ar to a cooled (ꢀ78 ꢁC) solution of the above imine in
4.3.3. 10-[N-((Z)-2-Bromo-2-butenyl)-N-methylamino]-5-(phenyl-
sulfonyl)-9,10-dihydro-6H-cyclohepta[b]indole (9). Amine 6 hydro-
chloride (84 mg, 0.16 mmol) in CH2Cl2 (2.4 mL, 0.07 M) was heated
at reflux in the presence of the second generation Grubbs catalyst
(7 mol %) for 2 h. The reaction mixture was diluted with a saturated
aqueous NaHCO3 solution (10 mL) and extracted with CH2Cl2
(3ꢂ10 mL). The combined organic extracts were dried and

4646
M.-L. Bennasar et al. / Tetrahedron 68 (2012) 4641e4648
concentrated, and the resulting residue was chromatographed
(85%); 1H NMR (300 MHz)
d 1.51 (s, 9H), 2.69 (s, 3H), 2.82e3.08 (m,
(97:3 hexanes/AcOEt) to give the title compound 9 as a light brown
2H), 3.28 (s, 3H), 5.04 (dm, J¼9 Hz, 1H), 5.16 (dm, J¼15 Hz, 1H), 5.53
(s, 2H), 5.72e5.90 (m, 2H), 7.19 (t, J¼7.5 Hz,1H), 7.24 (t, J¼7.5 Hz,1H),
7.42 (d, J¼7.5 Hz, 1H), 7.74 (d, J¼7.5 Hz, 1H); 13C NMR (75.4 MHz)
oil: 52 mg (65%); 1H NMR (400 MHz)
d
1.70 (d, J¼6 Hz, 3H), 2.03 (s,
3H), 2.40 (m, 1H), 2.60 (m, 1H), 3.12 and 3.22 (2d, J¼14.0 Hz, 2H),
3.95 (m, 3H), 5.84 (m, 3H), 7.23 (m, 2H), 7.33 (m, 2H), 7.46 (m, 1H),
7.62 (m, 2H), 7.82 (d, J¼7.5 Hz, 1H), 8.17 (d, J¼8.0 Hz, 1H); 13C NMR
d
28.8 (CH3), 29.2 (CH3), 35.5 (CH2), 52.1 (CH), 56.3 (CH3), 74.1 (CH2),
79.8 (C), 110.1 (CH), 111.2 (C), 117.4 (CH2), 119.8 (CH), 121.4 (CH), 123.1
(CH), 124.9 (C), 127.5 (C), 135.4 (CH), 136.0 (C), 155.7 (C); ESI-HRMS
[MþNa]þ calcd for C20H27ClN2NaO3 401.1602, found 401.1619.
(74.5 MHz)
d 16.6 (CH3), 25.3 (CH2), 25.9 (CH2), 36.9 (CH3), 58.5
(CH), 63.2 (CH2), 115.4 (CH), 120.8 (CH), 123.6 (CH), 124.1 (C), 124.3
(CH), 125.5 (CH), 126.1 (2CH), 126.9 (C), 128.6 (CH), 128.7 (CH), 128.9
(2CH), 131.4 (C), 133.5 (CH), 136.5 (C), 136.6 (C), 138.2 (C); ESI-HRMS
[MþH]þ calcd for C24H26BrN2O2S 485.0892, found 485.0873.
4.4.3. 3-[1-(N-tert-Butoxycarbonyl-N-methylamino)-3-butenyl]-1-
(methoxymethyl)-2-(1-oxo-2-propenyl)indole (20). t-BuLi (1.7 M in
pentane, 0.6 mL, 1.02 mmol) was slowly added to a solution of 2-
chloroindole 19 (254 mg, 0.67 mmol) in THF (12 mL) cooled at
ꢀ78 ꢁC and the resulting mixture was stirred at ꢀ78 ꢁC for 30 min.
Acrolein (0.13 mL, 1.92 mmol) was added and the mixture was stir-
red at ꢀ78 ꢁC for 20 min. The reaction mixture was quenched with
10% aqueous NH4Cl (15 mL) and extracted with Et2O (3ꢂ15 mL). The
organic extracts were dried and concentrated and the resulting
residue was chromatographed (1:1 hexanes/AcOEt) to give the crude
carbinol. A solution of the above material in CH2Cl2 (15 mL) was
treated with MnO2 (0.58 g, 6.7 mmol) at rt overnight. The reaction
mixture was filtered through Celite and the filtrate was concentrated
to give ketone 20 as a light brown foam: 120 mg (45%); 1H NMR
4.3.4. 10-((Z)-2-Bromo-N-methyl-2-butenamido)-5-(phenyl-
sulfonyl)-9,10-dihydro-6H-cyclohepta[b]indole (13). The second
generation Grubbs catalyst (7 mol %) was added under Ar to a solu-
tion of amide 12 (50 mg, 0.09 mmol) in CH2Cl2 (2 mL) and the
resulting mixture was heated at reflux for 3 h. The reaction mixture
was concentrated and the residue was chromatographed (95:5
hexanes/AcOEt) to give the title compound 13 as a light brown foam:
41 mg (87%); 1H NMR (400 MHz, major rotamer)
d
1.82 (d, J¼6.8 Hz,
3H), 2.47 (s, 3H), 2.55 (m, 1H), 2.75 (m, 1H), 3.90 (m, 2H), 5.90 (br s,
1H), 5.99 (m, 2H), 6.20 (br q, J¼6.8 Hz, 1H), 7.20e7.45 (m, 5H), 7.52
(m, 1H), 7.67 (d, J¼7.2 Hz, 2H), 8.23 (d, J¼8 Hz, 1H); 13C NMR
(74.5 MHz)
d
16.3 (CH3), 25.1 (CH2), 28.9 (CH2), 32.9 (CH3), 49.3 (CH),
(300 MHz, major rotamer) d 1.47 (s, 9H), 2.75 (s, 3H), 2.80 (m, 2H),
115.6 (CH), 117.3 (C), 118.6 (CH), 124.4 (CH), 125.0 (CH), 126.1 (2CH),
129.1 (2CH), 129.2 (1CH), 130.2 (C), 130.7 (CH), 133.7 (CH), 136.5 (C),
137.2 (C), 138.5 (C), 166.6 (CO), one quaternary C not observed; ESI-
HRMS [MþH]þ calcd for C24H24BrN2O3S 499.0691, found 499.0695.
3.16 (s, 3H), 4.95 (dm, J¼9 Hz, 1H), 5.15 (dm, J¼15 Hz, 1H), 5.46 (d,
J¼8.8 Hz, 1H), 5.53 (d, J¼8.8 Hz, 1H), 5.57 (m, 2H), 6.08 (d, J¼9H, 1H),
6.18 (d, J¼15 Hz,1H), 6.81 (dd, J¼15 and 8.8 Hz), 7.22 (t, J¼7.5 Hz,1H),
7.35 (t, J¼7.5 Hz, 1H), 7.51 (d, J¼7.5 Hz, 1H), 7.85 (d, J¼7.5 Hz, 1H); 13C
NMR (75.4 MHz, major rotamer) d 28.8 (CH3), 29.8 (CH3), 36.4 (CH2),
4.4. Synthesis of cyclohepta[b]indole 21
52.3 (CH), 56.2 (CH3), 75.4 (CH2), 79.9 (C), 111.2 (CH), 117.6 (CH2),
118.1 (C), 121.7 (CH), 122.4 (CH), 124.9 (CH), 127.2 (C), 132.3 (CH2),
135.0 (CH), 135.4 (C), 138.0 (CH), 139.3 (C), 155.5 (C), 197.0 (C); ESI-
HRMS [MþNa]þ calcd for C23H30N2NaO4 421.2097, found 421.2089.
4.4.1. 3-[1-(N-tert-Butoxycarbonyl-N-methylamino)-3-butenyl]-1-
(methoxymethyl)indole (18). Methylamine (8 M in EtOH, 1.32 mL,
10.6 mmol) and AcOH (0.06 mL,1.06 mmol) were successively added
to a solution of aldehyde 1616 (0.2 g, 1.06 mmol) in CH2Cl2 (8 mL).
After being stirred at rt overnight, the reaction mixture was diluted
with CH2Cl2 (5 mL), basified with a saturated Na2CO3 solution, and
extracted with CH2Cl2 (3ꢂ10 mL). The organic extracts were dried
and concentrated to give the crude imine. Allylmagnesium bromide
(1 M in Et2O, 1.59 mL, 1.59 mmol) was added under Ar to a cooled
(ꢀ78 ꢁC) solution of the above material in anhydrous THF (25 mL),
and the mixture was stirred at rt overnight. The reaction mixture
was quenched with a 10% aqueous NH4Cl solution (10 mL) and
extracted with Et2O (3ꢂ10 mL). The organic extracts were dried and
concentrated to give the crude secondary amine. Et3N (0.85 mL,
6.08 mmol) and (Boc)2O (0.46 g, 2.12 mmol) were successively
added to a solution of the above material in MeOH (30 mL) and the
mixture was heated at reflux for 5 h. The solvent was removed and
the residue was diluted with CH2Cl2 (30 mL) and washed with 1 N
HCl (2ꢂ20 mL) and brine (2ꢂ20 mL). The organic solution was dried
and concentrated and the residue was chromatographed (85:15
hexanes/AcOEt) to give carbamate 18 as a light brown foam: 0.29 g
4.4.4. 10-(N-tert-Butoxycarbonyl-N-methylamino)-5-(methoxymet-
hyl)-9,10-dihydro-5H-cyclohepta[b]indole-6-one (21). The second
generation Grubbs catalyst (30 mg, 7 mol %) was added under Ar
to a solution of ketone 20 (0.2 g, 0.50 mmol) in CH2Cl2 (30 mL) and
the resulting mixture was heated at reflux overnight. The reaction
mixture was concentrated and the residue was chromatographed
(9:1 hexanes/AcOEt) to give 21 as a pale yellow foam: 120 mg
(65%); 1H NMR (300 MHz, major rotamer)
d 1.54 (s, 9H), 2.66 (s,
3H), 2.85e3.05 (m, 2H), 3.32 (s, 3H), 6.01 (d, J¼10.5 Hz,1H), 6.10 (d,
J¼10.5 Hz, 1H), 6.32 (d, J¼11 Hz, 1H), 6.65 (m, 1H), 7.18e7.30 (m,
2H), 7.44 (t, J¼7.5 Hz, 1H), 7.56 (d, J¼7.5 Hz, 1H), 7.71 (m, 1H); 13C
NMR (75.4 MHz, major rotamer)
d 28.8 (CH3), 31.7 (CH3), 33.3
(CH2), 49.7 (CH), 56.4 (CH3), 75.9 (CH2O), 80.1 (C), 111.5 (CH), 121.9
(CH), 122.2 (CH), 123.6 (C), 126.4 (C), 127.6 (CH), 134.8 (CH), 139.4
(CH), 140.2 (C), 155.5 (C), 185.4 (C). One quaternary C was not
observed; ESI-HRMS calcd for C21H26N2O4 370.1892, found
370.1910.
(80%); 1H NMR (300 MHz, mixture of rotamers)
d
1.50 and 1.57 (2br
4.4.5. 5-(Methoxymethyl)cyclohepta[b]indol-6-one
(22). Yellow
s, 9H), 2.50 (br, 3H), 2.71 (m, 2H), 3.24 (s, 3H), 5.08 (br d, J¼10.5 Hz,
1H), 5.17 (dm, J¼17.1 Hz, 1H), 5.43 (s, 2H), 5.60 and 5.86 (2br m, 2H),
7.08 (s, 1H), 7.14 (td, J¼7.5 and 1 Hz, 1H), 7.25 (td, J¼7.5 and 1 Hz,1H),
7.45 (d, J¼7.5 Hz, 1H), 7.64 (br d, J¼7.5 Hz, 1H); 13C NMR (75.4 MHz,
amorphous solid. 1H NMR (400 MHz)
d
3.37 (s, 3H), 6.52 (s, 2H), 7.01
(m, 1H), 7.24e7.38 (m, 2H), 7.42 (tm, J¼8 Hz, 1H), 7.62 (tm, J¼8 Hz,
1H), 7.75 (d, J¼8 Hz, 1H), 8.12 (m, 2H); 13C NMR (100.5 MHz)
d 56.2
(CH3), 75.6 (CH2), 112.2 (CH), 120.8 (CH), 122.7 (CH), 124.9 (CH),
125.1 (C), 126.0 (C), 128.4 (CH), 129.3 (CH), 135.3 (CH), 138.0 (CH),
140.3 (C), 140.5 (C), 179.7 (C); ESI-HRMS calcd for C15H13NO2
239.0946, found 239.0944.
mixture of rotamers)
d 27.9 (CH3), 28.5 (CH3), 35.5 (CH2), 49.9 and
51.5 (CH), 55.9 (CH3), 77.3 (CH2), 79.1 (C), 109.7 (CH), 115.9 (C), 116.8
and 117.1 (CH2), 119.8 (CH), 120.3 (CH), 122.7 (CH), 126.0 (CH), 128.0
(C), 134.9 (CH), 136.9 (C), 155.9 (C).
4.5. Heck cyclizations
4.4.2. 3-[1-(N-tert-Butoxycarbonyl-N-methylamino)-3-butenyl]-2-
chloro-1-(methoxymethyl)indole (19). Operating as above, from al-
dehyde 1717 (0.3 g, 1.28 mmol) carbamate 19 was obtained as a light
brown foam after chromatography (85:15 hexanes/AcOEt): 412 mg
4.5.1. 4-(E)-Ethylidene-2-(methoxycarbonyl)-8-(phenylsulfonyl)-
2,3,4,5-tetrahydro-1,5-methano-1H-azonino[4,3-b]indole
(23). Pd(PPh3)4 (17 mg, 0.015 mmol), K3PO4 (96 mg, 0.45 mmol),

M.-L. Bennasar et al. / Tetrahedron 68 (2012) 4641e4648
4647
phenol (3.5 mg, 0.04 mmol), and Et3N (0.1 mL, 0.75 mmol) were
successively added to a solution of vinyl iodide 8 (87 mg,
0.15 mmol) in toluene (11 mL), and the resulting mixture was
heated at reflux for 12 h. The reaction mixture was diluted with
Et2O and washed with a saturated aqueous Na2CO3 solution and
brine. The organic layer was dried and concentrated. The
resulting residue was chromatographed (hexanes and 95:5
hexanes/EtOAc) to give the title compound 23 as a light brown
oil: 43 mg (65%); 1H NMR (400 MHz, assignment aided by
assignment aided by gHSQC)
d
13.9 (CH3), 37.6 (C-13), 34.1 (NCH3),
35.9 (C-5), 51.7 (C-1), 116.4 (CH), 117.0 (CH), 118.1 (C-7), 124.5 (C),
124.6 (CH), 125.6 (CH), 126.6 (2CH), 127.3 (C), 129.3 (2CH), 130.1 (C),
132.8 (CH), 134.0 (CH), 134.6 (C-6), 134.9 (C), 136.4 (C), 138.5 (C),
116.7 (CO); ESI-HRMS [MþH]þ calcd for C24H23N2O3S 419.1424,
found 419.1412.
Acknowledgements
gHSQC, 2:1 mixture of rotamers)
d
1.70 (dm, J¼6.4 Hz, 3H), 1.91
We thank the Ministerio de Economía y Competitividad, Spain,
for financial support (project CTQ2009-07175) and the University
of Barcelona for a grant to S.A.
(d, J¼13 Hz, 1H, 13-H), 2.25 (m, 1H, 13-H), 2.94 and 3.10 (major)
(2d, J¼13.5 Hz, 1H, 3-H), 3.67 (major) and 3.81 (2s, 3H, OCH3),
3.81 (masked, 1H, 5-H), 4.04 (major) and 4.17 (d, J¼13.5 Hz, 1H,
3-H), 5.37 (major) and 5.42 (2q, J¼6.4 Hz, 1H), 5.73 and 5.91
(major) (2 br s, 1H, 1-H), 6.05 (m, 1H), 7.31 (m, 1H), 7.34 (m, 1H),
7.36 (m, 2H), 7.49 (m, 2H), 7.67 (m, 2H), 7.85 (d, J¼8 Hz, 1H), 8.25
(d, J¼8 Hz, 1H); 13C NMR (74.5 MHz, assignment aided by gHSQC,
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2012.04.022.
major rotamer)
d 12.5 (CH3), 29.3 (C-13), 35.7 (C-5), 45.1 (C-1),
45.6 (C-3), 52.7 (OCH3), 115.7 (CH), 118.6 (C-7), 119.3 (C), 120.2
(CH), 120.3 (CH), 124.5 (CH), 125.6 (CH), 126.2 (C), 126.3 (2CH),
129.1 (2CH), 133.3 (C), 133.6 (CH), 134.8 (C-6), 136.1 (C), 136.9 (C),
138.2 (C), 155.1 (CO); ESI-HRMS [MþH]þ calcd for C25H25N2O4S
449.1529, found 449.1523.
References and notes
1. Joule, J. A. In Indoles, The Monoterpenoid Indole Alkaloids; Saxton, J. E., Ed.;
Wiley: New York, NY, 1983; Vol. 25, pp 232e239.
2. Andriantsiferana, M.; Besselievre, R.; Riche, C.; Husson, H.-P. Tetrahedron Lett.
ꢁ
1977, 2587e2590.
3. (a) Grierson, D. S.; Harris, M.; Husson, H.-P. Tetrahedron 1983, 39, 3683e3694;
(b) Bosch, J.; Rubiralta, M.; Domingo, A.; Bolos, J.; Linares, A.; Minguillon, C.;
4.5.2. 4-(Z)-Ethylidene-2-(methoxycarbonyl)-7-(phenylsulfonyl)-
ꢀ
ꢀ
1,2,3,4,5,6-hexahydro-1,5-ethenoazocino[4,3-b]indole
(24). PPh3
Amat, M.; Bonjoch, J. J. Org. Chem. 1985, 50, 1516e1522; (c) Bosch, J.; Rubiralta,
(13 mg, 0.05 mmol), Ag2CO3 (142 mg, 0.51 mmol), and Pd(OAc)2
(4 mg, 0.017 mmol) were successively added to a solution of vinyl
iodide 8 (98 mg, 0.17 mmol) in toluene (9 mL), and the resulting
mixture was stirred at 80 ꢁC for 1 h. The solvent was removed and
the resulting residue was dissolved in CH2Cl2 (10 mL) and washed
with H2O (5 mL). The organic extracts were dried and concen-
trated and the resulting residue was chromatographed (from cy-
clohexane to 94:6 cyclohexane/CH2Cl2) to give 23 (14 mg, 19%) and
the title compound 24 as a light brown oil: 33 mg (43%); 1H NMR
(400 MHz, assignment aided by gCOSY and gHSQC, 2:1 mixture of
ꢀ
M.; Bolos, J. Tetrahedron 1987, 43, 391e396; (d) Salas, M.; Joule, J. A. J. Chem. Res.,
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Miniprint 1990, 664e673; (e) Rubiralta, M.; Marco, M.-P.; Bolos, J.; Trape, J.
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4. For a more recent approach, see Amat, M.; Checa, B.; Llor, N.; Perez, M.; Bosch, J.
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Eur. J. Org. Chem. 2011, 898e907.
5. (a) Bennasar, M.-L.; Vidal, B.; Bosch, J. J. Am. Chem. Soc. 1993, 115, 5340e5341;
(b) Bennasar, M.-L.; Vidal, B.; Bosch, J. J. Org. Chem. 1997, 62, 3597e3609; For the
enantioselective version, see: (c) Bennasar, M.-L.; Zulaica, E.; Alonso, Y.; Bosch,
J. Tetrahedron: Asymmetry 2003, 14, 469e479.
6. For general reviews, see: (a) Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-
VCH: Weinheim, 2003; Vol. 2; (b) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104,
2199e2238.
€
7. For general reviews, see: (a) Brase, S.; de Meijere, A. In Metal-Catalyzed Cross-
rotamers)
d
1.58 (major) and 1.65 (2d, J¼6.4 Hz, 3H, CH3), 3.27 (br
Coupling Reactions; de Meijere, A., Diederich, F., Eds.; Wiley-WCH: New York,
NY, 2004; pp 217e316; (b) Zeni, G.; Larock, R. C. Chem. Rev. 2006, 106,
4644e4680.
s, 1H, 5-H), 3.30 (m, 2H, 6-H), 3.70 (major) and 3.76 (2s, 3H, OCH3),
3.72 (m, 1H, 3-H), 4.43 and 4.67 (2d, J¼15.2 Hz, 1H, 3-H), 5.39 (m,
1H, CH]ethylidene), 5.79 and 6.01 (major) (2d, J¼7.6 or 8 Hz, 1H,
1-H), 6.16 (t, J¼8.8 Hz, 1H, 13-H), 6.30 (m, 1H, 12-H), 7.26 (m, 2H),
7.40 (m, 2H), 7.53 (m, 1H), 7.70 (m, 3H), 8.20 (m, 1H); 13C NMR
8. For a preliminary communication of part of this work, see: Bennasar, M.-L.;
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Zulaica, E.; Sole, D.; Alonso, S. Synlett 2008, 667e670.
9. For the construction of polycyclic systems by sequential RCM and aryl or het-
eroaryl halide Heck cyclizations, see: (a) Grigg, R.; Sridharan, V.; York, M. Tet-
rahedron Lett. 1998, 39, 4139e4142; (b) Grigg, R.; York, M. Tetrahedron Lett.
2000, 41, 7255e7278; (c) Lautens, M.; Zunic, V. Can. J. Chem. 2004, 82,
399e407; (d) Enders, D.; Lenzen, A.; Backes, M.; Janeck, C.; Catlin, K.; Lannou,
M.-I.; Runsink, J.; Raabe, G. J. Org. Chem. 2005, 70, 10538e10551; (e) Sunder-
haus, J. D.; Dockendorff, C.; Martin, S. F. Org. Lett. 2007, 9, 4223e4226; (f) Ri-
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D. N.; Djuric, S. W. Org. Lett. 2007, 9, 5119e5122.
(74.5 MHz, assignment aided by gHSQC, major rotamer)
d 13.2
(CH3), 32.8 (C-6), 41.0 (C-3), 42.2 (C-5), 46.5 (C-1), 52.8 (OCH3),
114.4 (CH), 117.0 (C), 118.7 (CH), 123.0 (CH ethylidene), 123.7 (CH),
124.5 (CH), 126.2 (2CH), 129.2 (2CH), 129.5 (C), 132.0 (C-12), 133.4
(C-13), 133.6 (CH), 134.9 (C), 135.9 (C), 138.4 (C), 139.1 (C), 156.1
(CO); ESI-HRMS [MþH]þ calcd for C25H25N2O4S 449.1529, found
449.1527.
10. (a) Rawal, V. H.; Michoud, C. Tetrahedron Lett. 1991, 32, 1695e1698; (b) Rawal,
V. H.; Michoud, C.; Monestel, R. F. J. Am. Chem. Soc. 1993, 115, 3030e3031; (c)
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Rawal, V. H.; Iwasa, S. J. Org. Chem. 1994, 59, 2685e2686; (d) Sole, D.; Bonjoch,
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J.; García-Rubio, S.; Peidro, E.; Bosch, J. Chem.dEur. J. 2000, 6, 655e665; (e)
Eichberg, M. J.; Dorta, R. L.; Grotjahn, D. B.; Lamottke, K.; Schmidt, M.; Voll-
hardt, K. P. C. J. Am. Chem. Soc. 2001, 123, 9324e9337; (f) Mori, M.; Nakanishi,
M.; Kahishima, D.; Sato, Y. J. Am. Chem. Soc. 2003, 125, 9801e9807; (g) Dounay,
A. B.; Humphreys, P. G.; Overman, L. E.; Wrobleski, A. D. J. Am. Chem. Soc. 2008,
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131, 3472e3473.
4.5.3. 4-(E)-Ethylidene-2-methyl-3-oxo-8-(phenylsulfonyl)-2,3,4,5-
tetrahydro-1,5-methano-1H-azonino[4,3-b]indole (25). PPh3 (6 mg,
0.024 mmol), Pd(OAc)2 (1 mg, 0.004 mmol), proton sponge (1.7 mg,
0.008 mmol), and K2CO3 (12 mg, 0.09 mmol) were successively
added to a solution of vinyl bromide 13 (40 mg, 0.08 mmol) in
toluene (5 mL), and the resulting mixture was heated at reflux for
20 h. The solvent was removed and the resulting residue was dis-
solved in CH2Cl2 (5 mL) and washed with H2O (2ꢂ5 mL). The or-
ganic extracts were dried and concentrated and the resulting
residue was chromatographed (95:5 hexanes/AcOEt) to give the
title compound 25 as a light brown foam: 17 mg (50%); 1H NMR
11. Birman, V. B.; Rawal, V. H. J. Org. Chem. 1998, 63, 9146e9147.
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12. (a) Bennasar, M.-L.; Zulaica, E.; Sole, D.; Alonso, S. Chem. Commun. 2009,
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3372e3374; (b) Bennasar, M.-L.; Zulaica, E.; Sole, D.; Roca, T.; García-Díaz, D.;
Alonso, S. J. Org. Chem. 2009, 74, 8359e8368.
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13. Bennasar, M.-L.; Sole, D.; Zulaica, E.; Alonso, S. Org. Lett. 2011, 13, 2042e2045.
14. For instance, see: (a) Ban, Y.; Yoshida, K.; Goto, J.; Oishi, T.; Takeda, E. Tetra-
ꢁ
hedron 1983, 39, 3657e3668; (b) Gracia, J.; Casamitjana, N.; Bonjoch, J.; Bosch, J.
J. Org. Chem. 1994, 59, 3939e3951; (c) Saito, M.; Kawamura, M.; Hiroya, K.;
Ogasawara, K. J. Chem. Commun. 1997, 765e766.
(400 MHz, assignment aided by gHSQC)
d
1.90 (d, J¼7.2 Hz, 3H), 2.11
ꢀ
15. Bennasar, M.-L.; Zulaica, E.; Sole, D.; Alonso, S. Tetrahedron 2007, 63, 861e866.
16. Comins, D. L.; Killpack, M. O. J. Org. Chem. 1987, 52, 104e109.
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2001, 49, 881e886.
18. (a) Jeffery, T. Tetrahedron Lett. 1985, 26, 2667e2670; (b) Jeffery, T. Tetrahedron
1996, 52, 10113e10130.
(dd, J¼13 and 2 Hz, 1H, 13-H), 2.60 (dm, J¼13 Hz, 1H, 13-H), 2.82 (s,
3H, NCH3), 3.95 (m, 1H, 5-H), 4.88 (d, J¼6.5 Hz, 1H, 1-H), 5.95 (dd,
J¼12 and 6 Hz, 1H, 6-H), 6.90 (q, J¼7.2 Hz, 1H), 7.30e7.40 (m, 4H),
7.55 (m, 3H), 7.65 (m, 2H), 8.25 (d, J¼8 Hz, 1H); 13C NMR (74.5 MHz,

4648
M.-L. Bennasar et al. / Tetrahedron 68 (2012) 4641e4648
19. Rutherford, J. L.; Rainka, M. P.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
15618e15619.
23. Owczarczyk, Z.; Lamaty, F.; Vawter, E. J.; Negishi, E. J. Am. Chem. Soc. 1992, 114,
10091e10092.
ꢀ
20. See also: (a) Sole, D.; Urbaneja, X.; Bonjoch, J. Tetrahedron Lett. 2004, 45, 3131e3135;
24. A seven-membered palladacycle formed by coordination of a sulfonyl oxygen
atom has been proposed as a potential transition state in some Suzuki re-
actions: Broutin, P.-E.; Colobert, F. Org. Lett. 2005, 7, 3737e3740.
25. Miyaura, N.; Ishikawa, M.; Suzuki, A. Tetrahedron Lett. 1992, 33, 2571e2574.
ꢀ
(b) Sole, D.; Urbaneja, X.; Bonjoch, J. Adv. Synth. Catal. 2004, 346, 1646e1650.
21. The configuration of the ethylidene substituent was established by NOESY
experiments.
ꢀ
22. (a) Rawal, V. H.; Michoud, C. J. Org. Chem. 1993, 58, 5583e5584; (b) Feutren, S.;
McAlonan, H.; Montgomery, D.; Stevenson, P. J. J. Chem. Soc., Perkin Trans. 1
2000, 1129e1137.
26. Sole, D.; Urbaneja, X.; Cordero-Vargas, A.; Bonjoch, J. Tetrahedron 2007, 63,
10177e10184.
27. Bachman, G. B. J. Am. Chem. Soc. 1933, 55, 4279e4284.