Facile synthesis of azocino[4,3-b]indoles by ring-closing metathesis

Article abstract of DOI:10.1016/j.tet.2006.11.043

The azocino[4,3-b]indole system, tricyclic substructure of the indole alkaloids apparicine and ervaticine, is efficiently assembled by ring-closing metathesis of 2-allyl-3-(allylaminomethyl)indoles. The metathesis sites are introduced into the indole nucl

Full text of DOI:10.1016/j.tet.2006.11.043

Tetrahedron 63 (2007) 861–866
Facile synthesis of azocino[4,3-b]indoles by ring-closing metathesis
*
M.-Lluısa Bennasar, Ester Zulaica, Daniel Sole and Sandra Alonso
€
ꢀ
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, Barcelona 08028, Spain
Received 24 October 2006; revised 13 November 2006; accepted 16 November 2006
Available online 11 December 2006
Abstract—The azocino[4,3-b]indole system, tricyclic substructure of the indole alkaloids apparicine and ervaticine, is efficiently assembled
by ring-closing metathesis of 2-allyl-3-(allylaminomethyl)indoles. The metathesis sites are introduced into the indole nucleus by reductive
amination of a 3-formyl derivative with allylamine, followed by a-lithiation with subsequent electrophilic trapping with acrolein.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
indole alkaloid known for 40 years but still awaiting its first
total synthesis,8 and also the unprecedented 2-acylindole
analogue ervaticine.9
Ruthenium-catalyzed ring-closing metathesis (RCM)1 has
emerged as a powerful tool for the construction of a great
variety of carbo- and heterocycles from acyclic precursors.2
In particular, the RCM methodology has turned out to be
very useful for the synthesis of medium-sized rings,3 which
is generally problematic due to disfavored entropic factors
and transannular interactions. Our interest in the develop-
ment of indole annulation methodologies led us to consider
RCM reactions of indole-containing dienes4,5 for the effi-
cient construction of medium-sized indolo 2,3-fused carbo-
and azacycles, which are common structural arrangements
in many natural and synthetic bioactive compounds.6 In this
paper we report a direct synthetic approach to the azo-
cino[4,3-b]indole system I by RCM of appropriate 2,3-di-
alkenylindoles incorporating a nitrogen atom in the tether
linking the two double bonds (Scheme 1). It should be noted
that I constitutes the tricyclic substructure of apparicine,7 an
2. Results and discussion
We set out to explore the feasibility of the protocol using
model RCM precursors unfunctionalized at the benzylic
indole a-position, such as 2-allyl-3-(allylaminomethyl)-
indoles 3.10 For the preparation of these substrates, a fast
formylation–reductive amination sequence starting from the
known 2-allylindole 111 was envisaged (Scheme 2). A strong
electron-withdrawing benzenesulfonyl group was placed at
the indole nitrogen to guarantee the stability of the proposed
gramine-type intermediates. Thus, Friedel–Crafts reaction
of 1 with Cl2CHOMe in the presence of TiCl4 gave the alde-
hyde 2 (90%), which was subjected to reductive amination
with allylamine, followed by reaction of the resulting sec-
ondary amine with (t-BuOCO)2O or TsCl. In this manner,
the required RCM substrates 3a or 3b, bearing different
R
N
NR
6
CHO
N
N
X
X
PG
PG
a
I
b,c
N
N
SO2Ph
SO2Ph
PG = SO2Ph, MOM
R = Boc, Ts
N
1
2
X = H,H; OTBDMS, H; O
R
N
R
N
N
H
X
d
X = CH2 Apparicine
6
X = O Ervaticine
N
N
SO2Ph
SO2Ph
a R = Boc
b R = Ts
Scheme 1. Synthetic plan.
3
4
Scheme 2. Reagents and conditions: (a) Cl2CHOMe, TiCl4, CH2Cl2,
ꢀ78 ꢁC, 2 h, 90%; (b) allylamine, NaBH(OAc)3, AcOH, rt, overnight; (c)
(t-BuOCO)2O, 4:1 MeOH–Et3N, reflux, 4 h, 65% (3a) or TsCl, Et3N,
CH2Cl2, rt, overnight 65% (3b); (d) (PCy3)2(Cl)2Ru]CHPh, CH2Cl2,
reflux, overnight, 60% (4a), 89% (4b).
Keywords: Ring-closing metathesis; Indole; Indole alkaloids.
* Corresponding author. Tel.: +34934024540; fax: +34934024539; e-mail:
bennasar@ub.edu
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.11.043

862
M.-L. Bennasar et al. / Tetrahedron 63 (2007) 861–866
protecting groups at the aliphatic nitrogen, were obtained in
65% overall yield from 2. Satisfactorily, ring closure of the
N-Boc diene 3a took place in refluxing dichloromethane in
the presence of the first generation Grubbs catalyst to give
the azocino[4,3-b]indole 4a in 60% yield. The N-tosyl deriv-
ative 3b proved to be a better substrate as it led to 4b in
a higher yield (89%).
some synthetic intermediates due to the lower electron-
withdrawing character of this moiety. Thus, we turned to
aldehyde 1014 (Scheme 5), which was converted into the
allylaminomethyl derivatives 11 under the usual conditions.
As the tosyl compound 11b partially decomposed under
chromatographic purification, we decided to continue the
synthesis only with the more stable N-Boc derivative 11a,
which could be isolated in a reproducible 72% yield.
With model azocino[4,3-b]indoles in hand, we sought to
elaborate C-6 functionalized derivatives simply by extend-
ing the chemistry outlined above to an O-protected 2-(1-
hydroxyallyl)indole. To this end, we selected silyl ether 6,
which was easily prepared from aldehyde 5,12 by reaction
with vinylmagnesium bromide followed by protection of
the resulting alcohol with tert-butyldimethylsilyl chloride
(63% overall yield, Scheme 3). Disappointingly, we were
not able to introduce the formyl group needed for the reduc-
tive amination step since 6 gave only a complex mixture
upon subjection to the above Friedel–Crafts protocol.
CHO
NR
c
a,b
N
from 11a
N
MOM
MOM
10
11
a R = Boc
b R = Ts
Boc
N
NBoc
f
N
N
X
X
MOM
MOM
a, b
12 X = H, OH
e
CHO
15 X = H, OTBDMS
16 X = O
d
13 X = H, OTBDMS
14 X = O
N
N
OTBDMS
SO2Ph
SO2Ph
6
5
Boc
N
CHO
N
17 X = H, OTBDMS
18 X = O
g
N
X
MOM
OTBDMS
SO2Ph
Scheme 5. Reagents and conditions: (a) allylamine, NaBH(OAc)3, AcOH,
rt, overnight; (b) (t-BuOCO)2O, 4:1 MeOH–Et3N, reflux, 4 h, 72% (11a)
or TsCl, Et3N, CH2Cl2, rt, overnight (11b); (c) t-BuLi, THF, ꢀ78 ꢁC, 2 h,
then acrolein, ꢀ78 ꢁC, 3.5 h, 79%; (d) MnO2, CH2Cl2, rt, 60 h, 64%; (e)
TBDMSCl, DMF, imidazole, 55 ꢁC, overnight, 64%; (f) (PCy3)2(Cl)2Ru]
CHPh, CH2Cl2, reflux, overnight, 85% (15) or (Im)(PCy3)(Cl)2Ru]CHPh,
CH2Cl2, rt, overnight, 86% (16); (g) H2, Pd/C, MeOH, 12 h, 80% (17),
82% (18).
Scheme 3. Reagents and conditions: (a) BrMgCH]CH2, THF, ꢀ78 ꢁC–rt,
overnight; (b) TBDMSCl, DMF, imidazole, 55 ꢁC, overnight, 63%.
This unsuccessful result prompted us to change the order of
the synthetic steps. Functionalization at the 2-position of
a properly 3-substituted indole by a-metalation followed
by electrophilic trapping seemed to be the logical solution.
With this aim, we focused our attention on 3-(aminomethyl)-
indoles 8 and 9, which were available from indole-3-carb-
aldehyde 713 through reductive amination techniques, using
tosylamine or, as above, allylamine followed by acylation
(Scheme 4). Unfortunately, treatment of these substrates with
either LDA, sec-BuLi or tert-BuLi in THF under a variety
of experimental conditions, followed by addition of DMF,
HCOOMe, or acrolein led to the recovery of the starting
product.
We were pleased to find that the desired a-lithiation did take
place from 11a upon treatment with tert-BuLi in THF
at ꢀ78 ꢁC. After quenching with acrolein, the unstable alco-
hol 12 was isolated (79%) and immediately protected as the
tert-butyldimethylsilyl ether 13 (64%) or, alternatively, oxi-
dized with MnO2 (64%) to the ketone 14. Satisfactorily,
when 13 was subjected to the previously used RCM condi-
tions (first generation Grubbs catalyst in refluxing dichloro-
methane) the expected tricyclic compound 15 was obtained
in good yield (85%). However, no cyclization was observed
from ketone 14 under the above protocol, probably due to the
presence of an electron-poor double bond, and only dimeric
products coming from intermolecular metathesis reactions
were formed. This problem was circumvented simply by
using the more efficient second generation Grubbs catalyst
at room temperature, leading to tricyclic ketone 16 in 86%
yield. Finally, the saturated forms of the eight-membered
heterocycles 17 and 18 were obtained by catalytic hydro-
genation over Pd/C.
NHTs
a
CHO
b,c
NR
N
N
N
SO2Ph
SO2Ph
SO2Ph
8
7
9
a R = Boc
b R = Ts
Scheme 4. Reagents and conditions: (a) TsNH2, toluene, reflux, 24 h, then
NaBH4, MeOH, rt, 24 h, 70%; (b) allylamine, NaBH(OAc)3, AcOH, rt,
overnight; (c) (t-BuOCO)2O, 4:1 MeOH–Et3N, reflux, 4 h, 68% (9a) or
TsCl, Et3N, CH2Cl2, rt, overnight 67% (9b).
3. Conclusion
We reasoned that the replacement of the indole protecting
group by a methoxymethyl (MOM) group could facilitate
the a-lithiation, despite a probable reduction in stability of
We have developed a new synthetic route to the azocino[4,3-
b]indole system15,16 relying on RCM of 2-allyl-3-(allyl-
aminomethyl)indoles. The efficiency of the cyclization

M.-L. Bennasar et al. / Tetrahedron 63 (2007) 861–866
863
combined with the easy preparation of the dienic precursors
from simple indolic derivatives make this strategy attractive
for the construction of medium-sized indolo 2,3-fused
carbo- and azacycles, which are scaffolds found in many bio-
active compounds.
7.20–7.65 (m, 6H), 7.70 (m, 2H), 8.20 (d, J¼7.5 Hz, 1H);
13C NMR (major rotamer) d 28.4 (3CH3), 29.9 (CH2), 38.5
(CH2), 47.0 (CH2), 79.9 (C), 115.0 (CH), 115.9 (CH2), 116.2
(CH2), 119.3 (CH), 123.7 (CH), 124.5 (CH), 126.2 (2CH),
129.0 (2CH), 129.8 (C), 133.4 (CH), 133.5 (CH), 134.9
(CH), 136.5 (C), 136.9 (C), 138.7 (C), 155.5 (CO); HRMS
calcd for C26H30N2O4S 466.1926, found 466.1932.
4. Experimental
4.1.3. 2-Allyl-3-[(N-allyl-N-tosylamino)methyl]-1-(phenyl-
sulfonyl)indole (3b). Aldehyde 2 (0.33 g, 1.0 mmol) was
allowed to react as above with allylamine and the resulting
secondary amine (0.32 g) was dissolved in CH2Cl2 (10 mL)
and treated with tosyl chloride (0.19 g, 1.0 mmol) and Et3N
(0.14 mL, 1.0 mmol) at rt overnight. The reaction mixture
was diluted with CH2Cl2 and washed with 1 N HCl and brine.
The organic extracts were dried and concentrated and the
residue was chromatographed (flash, CH2Cl2) to give 3b:
4.1. General methods
All nonaqueous reactions were performed under an argon
atmosphere. All solvents were dried by standard methods.
Reaction courses and product mixtures were routinely moni-
tored by TLC on silica gel (precoated F254 Merck plates).
Drying of organic extracts was carried out over anhydrous
Na2SO4. The solvents were evaporated under reduced pres-
sure with a rotary evaporator. Flash chromatography was
carried out on SiO2 (silica gel 60, SDS, 0.04–0.06 mm).
Melting points are uncorrected. Unless otherwise indicated,
NMR spectra were recorded in CDCl3 at 300 MHz (1H) or
75.4 MHz (13C) using Me4Si as an internal reference.
1
0.34 g (65%); mp 118 ꢁC (Et2O); H NMR d 2.44 (s, 3H),
3.52 (d, J¼6.3 Hz, 2H), 3.76 (dm, J¼6.0 Hz, 2H), 4.36 (s,
2H), 4.66 (dd, J¼17.0, 1.5 Hz, 1H), 4.72 (dd, J¼10.0,
1.5 Hz, 1H), 4.92 (dd, J¼17.0, 1.5 Hz, 1H), 4.99 (dd,
J¼10.0, 1.5 Hz, 1H), 5.23 (m, 1H), 5.93 (m, 1H), 7.25–7.75
(m, 12H), 8.20 (d, J¼7.5 Hz, 1H); 13C NMR d 21.5 (CH3),
29.9 (CH2), 41.5 (CH2), 49.4 (CH2), 114.9 (CH), 115.5 (C),
116.3 (CH2), 118.1 (CH2), 119.5 (CH), 123.8 (CH), 124.7
(CH), 126.2 (2CH), 127.2 (2CH), 129.0 (2CH), 129.1 (C),
129.7 (2CH), 132.4 (CH), 133.6 (CH), 134.7 (CH), 136.5
(C), 137.2 (C), 139.2 (C), 139.7 (C), 143.4 (C). Anal. Calcd
for C28H28N2O4S2: C, 64.59%; H, 5.41%; N, 5.38%. Found:
C, 64.67%; H, 5.43%; N, 5.35%.
4.1.1. 2-Allyl-1-(phenylsulfonyl)-3-indolecarbaldehyde
(2). 2-Allylindole 111 (0.7 g, 2.3 mmol) in CH2Cl2 (6 mL)
was added to a solution of TiCl4 (0.51 mL, 4.7 mmol) and
Cl2CHOCH3 (0.4 mL, 4.7 mmol) in CH2Cl2 (6 mL)
at ꢀ78 ꢁC, and the resulting mixture was stirred at ꢀ78 ꢁC
for 2 h. The reaction mixture was diluted with H2O, basified
with 10% aqueous Na2CO3, and extracted with CH2Cl2. The
organic extracts were dried and concentrated and the residue
was purified by flash chromatography (9:1 hexanes–AcOEt)
to give aldehyde 2: 0.69 g (90%); 1H NMR d 4.22 (m, 2H),
5.05 (dm, J¼17.0, 1.1 Hz, 1H), 5.12 (dm, J¼10.0, 1.1 Hz,
1H), 6.05 (m, 1H), 7.34–7.65 (m, 5H), 7.86 (m, 2H), 8.17
(m, 1H), 8.22 (m, 1H), 10.26 (s, 1H); 13C NMR d 29.5
(CH2), 114.3 (CH), 117.6 (CH2), 119.5 (C), 121.4 (CH),
125.1 (CH), 125.6 (CH), 126.0 (C), 126.6 (2CH), 129.4
(2CH), 134.2 (CH), 134.4 (CH), 135.9 (C), 138.4 (C), 148.8
(C), 185.6 (CO). Anal. Calcd for C18H15NO3S$1/4H2O:
C, 65.52%; H, 4.73%; N, 4.24%. Found: C, 65.81%;
H, 4.86%; N, 4.12%.
4.1.4. 2-(tert-Butoxycarbonyl)-7-(phenylsulfonyl)-1,2,3,6-
tetrahydroazocino[4,3-b]indole (4a). (PCy3)2(Cl)2Ru]
CHPh (first generation Grubbs catalyst, 10 mol %) was added
under Ar to a solution of amine 3a (90 mg, 0.19 mmol) in
anhydrous CH2Cl2 (5 mL) and the resulting mixture was
heated at reflux overnight. The reaction mixture was filtered
and concentrated. Flash chromatography of the crude residue
(1:1 hexanes–AcOEt) gave 4a: 50 mg (60%); 1H NMR (1:1
mixture of rotamers) d 1.25 and 1.44 (2s, 9H), 3.82 (m, 2H),
3.88 and 4.02 (2br s, 2H), 4.55 and 4.68 (2s, 2H), 5.60 and
5.71 (2m, 1H), 5.85 (m, 1H), 7.22–7.53 (m, 7H), 7.73 (m,
1H), 8.20 (m, 1H); 13C NMR d 23.4 (CH2), 28.3 (3CH3),
42.6 (CH2), 45.9 and 46.5 (CH2), 79.9 (C), 114.8 (CH),
117.8 (CH), 118.6 (C), 123.3 (CH), 124.2 (CH), 126.2
(2CH), 127.1 (CH), 128.2 (CH), 129.0 (C), 129.1 (2CH),
133.5 (CH), 136.0 (2C), 139.0 (C), 155.0 (CO). Anal. Calcd
for C24H26N2O4S$1/2H2O: C, 64.36%; H, 6.08%; N, 6.25%.
Found: C, 64.36%; H, 5.94%; N, 6.12%.
4.1.2. 2-Allyl-3-[(N-allyl-N-tert-butoxycarbonylamino)-
methyl]-1-(phenylsulfonyl)indole (3a). Allylamine (0.15 mL,
2.0 mmol), NaBH(OAc)3 (0.64 g, 3.0 mmol), and AcOH
(0.06 mL, 1.1 mmol) were successively added to aldehyde
2 (0.33 g, 1.0 mmol) in CH2Cl2 (8 mL), and the mixture
was stirred at rt overnight. The reaction mixture was diluted
with H2O, basified with solid Na2CO3, and extracted with
CH2Cl2. The organic extracts were dried and concentrated
and the resulting residue was purified by flash chromatography
(98:2 CH2Cl2–MeOH) to give the secondary amine: 0.32 g.
This compound was dissolved in MeOH (8 mL), treated with
Et3N (2 mL) and (t-BuOCO)2O (0.32 g, 1.46 mmol), and the
resulting mixture was heated at reflux for 4 h. The solvent was
removed and the residue was dissolved in CH2Cl2 (15 mL) and
washed successively with 1 N HCl and brine. The organic ex-
tracts were dried and concentrated and the residue was purified
by flash chromatography (CH2Cl2) to give 3a: 0.30 g (65%);
1H NMR (5:1 mixture of rotamers, major rotamer) d 1.49 (s,
9H), 3.40 (br s, 2H), 3.83 (br d, J¼6.0 Hz, 2H), 4.55 (s, 2H),
4.90 (m, 2H), 5.01 (m, 2H), 5.60 (m, 1H), 5.95 (m, 1H),
4.1.5. 7-(Phenylsulfonyl)-2-tosyl-1,2,3,6-tetrahydroazo-
cino[4,3-b]indole (4b). Operating as above, from amine
3b (0.1 g, 0.19 mmol) 4b was obtained: 80 mg (89%);
1H NMR (1H COSY) d 2.40 (s, 3H, Me), 3.76 (d,
J¼6.6 Hz, 2H, 3-H), 3.98 (d, J¼6.9 Hz, 2H, 6-H), 4.51 (s,
2H, 1-H), 5.42 (m, 1H, 4-H), 5.92 (m, 1H, 5-H), 7.20–7.70
(m, 12H, Ar), 8.20 (d, J¼7.5 Hz, 1H, 8-H); 13C NMR
(Hetcor) d 21.5 (CH3), 25.0 (C-6), 42.1 (C-1), 45.0 (C-3),
114.8 (C-8), 115.3 (C-11b), 117.9 (C-11), 123.6 (C-10),
124.6 (C-9), 125.2 (C-4), 126.1 (2CH), 127.0 (2CH), 129.0
(C-11a), 129.2 (2CH), 129.6 (2CH), 129.8 (C-5), 133.7
(CH), 136.0 (2C), 136.4 (C), 138.8 (C), 143.3 (C); HRMS
calcd for C26H24N2O4S2 492.6118, found 492.6110.

864
M.-L. Bennasar et al. / Tetrahedron 63 (2007) 861–866
4.1.6. 2-[1-(tert-Butyldimethylsilyloxy)-2-propenyl]-1-
(phenylsulfonyl)indole (6). BrMgCH]CH2 (1 M solution
in THF, 2.96 mmol) was added to a solution of aldehyde
512 (0.65 g, 2.28 mmol) in THF (15 mL) at ꢀ78 ꢁC and
the resulting mixture was stirred at rt overnight. The reaction
mixture was diluted with 10% aqueous NH4Cl and extracted
with Et2O. The organic extracts were dried and concentrated
and the residue was purified by flash chromatography (9:1
hexanes–AcOEt) to give 1-(phenylsulfonyl)-2-(1-hydroxy-
2-propenyl)indole (0.57 g). This compound was dissolved
in DMF (5 mL) and treated with TBDMSCl (0.40 g,
2.7 mmol) and imidazole (0.30 g, 4.5 mmol) at 55 ꢁC over-
night. The reaction mixture was diluted with H2O and
extracted with Et2O. The organic extracts were dried and
concentrated. Flash chromatography (95:5 hexanes–AcOEt)
2H), 4.52 (br s, 2H), 5.10 (m, 2H), 5.65 (m, 1H), 7.20–
7.65 (m, 7H), 7.85 (m, 2H), 8.05 (d, J¼7.5 Hz, 1H);
13C NMR d 28.3 (3CH3), 40.8 (CH2), 48.0 (CH2), 79.9
(C), 113.5 (CH), 116.3 (CH2), 119.6 (CH), 120.3 (CH),
123.2 (CH), 124.6 (CH), 124.8 (CH), 126.5 (2CH), 128.8
(C), 129.1 (2CH), 133.4 (CH), 133.7 (CH), 135.3 (C),
137.9 (C), 155.3 (CO); HRMS calcd for C23H26N2O4S
426.1613, found 426.1610.
4.1.9. 3-[(N-Allyl-N-tosyl)aminomethyl]-1-(phenylsul-
fonyl)indole (9b). Aldehyde 7 (0.65 g, 2.3 mmol) was
allowed to react as above with allylamine and the resulting
secondary amine was dissolved in CH2Cl2 (12 mL) and
treated with tosyl chloride (0.33 g, 1.75 mmol) and Et3N
(0.25 mL, 1.75 mmol) at rt overnight. The reaction mixture
was diluted with CH2Cl2 and washed with 1 N HCl and brine
prior to drying and solvent evaporation. The resulting resi-
due was purified by flash chromatography (1:1 hexanes–
CH2Cl2) to give 9b: 0.74 g (67%); mp 108 ꢁC (Et2O);
1H NMR d 2.44 (s, 3H), 3.70 (d, J¼6.3 Hz, 2H), 4.43 (s,
2H), 4.90 (m, 2H), 5.37 (m, 1H), 7.25–7.95 (m, 13H), 8.01
(d, J¼7.5 Hz, 1H); 13C NMR d 21.4 (CH3), 41.8 (CH2),
49.5 (CH2), 113.3 (CH), 117.2 (C), 118.9 (CH2), 120.1
(CH), 123.4 (CH), 125.0 (CH), 125.3 (CH), 126.4 (2CH),
126.9 (2CH), 129.1 (2CH), 129.5 (C), 129.6 (2CH), 131.9
(CH), 133.7 (CH), 135.1 (C), 136.7 (C), 137.7 (C), 143.4
(C). Anal. Calcd for C25H24N2O4S2: C, 62.48%; H, 5.03%;
N, 5.82%. Found: C, 62.58%; H, 5.21%; N, 5.69%.
1
of the residue gave 6: 0.61 g (63%); H NMR d ꢀ0.01 and
0.10 (2s, 6H), 0.95 (s, 9H), 5.15 (d, J¼10.0 Hz, 1H), 5.40
(d, J¼15 Hz, 1H), 5.90 (br s, 1H), 6.20 (m, 1H), 6.85 (s,
1H), 7.25–7.50 (m, 6H), 7.60 (m, 2H), 8.15 (d, J¼7.5 Hz,
1H); 13C NMR d ꢀ4.93 and ꢀ4.78 (2CH3), 18.3 (C), 25.8
(3CH3), 69.5 (CH), 109.8 (CH), 114.5 (CH2), 115.0 (CH),
120.8 (CH), 123.8 (CH), 124.3 (CH), 126.3 (2CH), 129.0
(2CH), 129.9 (C), 133.6 (CH), 137.7 (C), 138.6 (C), 139.8
(CH), 144.4 (C); HRMS calcd for C23H29NO3SSi
427.1637, found 427.1640.
4.1.7. 1-(Phenylsulfonyl)-3-(tosylaminomethyl)indole (8).
A solution of aldehyde 713 (0.5 g, 1.75 mmol) and tosyl-
amine (0.9 g, 5.25 mmol) in dry toluene (15 mL) was heated
at reflux (Dean–Stark) for 24 h. The solvent was removed
and the residue was dissolved in MeOH (10 mL) and treated
with NaBH4 (66 mg, 1.75 mmol) at rt for 24 h. The solvent
was removed and the residue was diluted with H2O and
extracted with Et2O. The organic extracts were dried and
concentrated and the resulting residue was purified by flash
chromatography (6:4 hexanes–AcOEt) to give tosylamine 8:
4.1.10. 3-[(N-Allyl-N-tert-butoxycarbonyl)aminomethyl]-
1-(methoxymethyl)indole (11a). Aldehyde 1014 (1.75 g,
9.2 mmol) in CH2Cl2 (30 mL) was allowed to react with al-
lylamine (1.41 mL, 18.8 mmol) and then with (t-BuOCO)2O
(3.67 g, 16.8 mmol) as described in Section 4.1.8. After
work-up and flash chromatography (7:3 hexanes–AcOEt),
1
11a was obtained: 2.20 g (72%); H NMR (50 ꢁC) d 1.50
1
0.54 g (70%); H NMR (CDCl3, 300 MHz) d 2.41 (s, 3H),
(s, 9H), 3.21 (s, 3H), 3.74 (br s, 2H), 4.59 (s, 2H), 5.10 (m,
2H), 5.47 (s, 2H), 5.73 (m, 1H), 7.08 (s, 1H), 7.10–7.30
(m, 2H), 7.46 (d, J¼8.0 Hz, 1H), 7.69 (d, J¼7.5 Hz, 1H);
13C NMR (50 ꢁC) d 28.5 (3CH3), 40.6 (CH2), 47.9 (CH2),
55.8 (CH3), 77.3 (CH2), 79.6 (C), 109.8 (CH), 113.0 (C),
116.0 (CH2), 119.6 (CH), 120.1 (CH), 122.4 (CH), 127.1
(CH), 128.2 (C), 134.1 (CH), 136.9 (C), 155.4 (CO). Anal.
Calcd for C19H26N2O3$1/4H2O: C, 68.14%; H, 7.97%; N,
8.36%. Found: C, 68.30%; H, 8.07%; N, 8.26%.
4.22 (d, J¼6.0 Hz, 1H), 5.04 (br s, 2H), 7.20–7.90 (m,
13H); 13C NMR d 21.5 (CH3), 38.6 (CH2), 113.4 (CH),
117.6 (C), 119.6 (CH), 123.3 (CH), 124.5 (CH), 125.0
(CH), 126.3 (2CH), 126.6 (2CH), 129.2 (2CH), 129.6
(2CH, C), 133.8 (CH), 136.1 (C), 137.8 (C), 138.9 (C),
143.4 (C); HRMS calcd for C22H20N2O4S2 440.0864, found
440.0857.
4.1.8. 3-[(N-Allyl-N-tert-butoxycarbonyl)aminomethyl]-
1-(phenylsulfonyl)indole (9a). Allylamine (0.34 mL,
4.6 mmol), NaBH(OAc)3 (1.46 g, 6.9 mmol), and AcOH
(0.13 mL, 2.3 mmol) were successively added to aldehyde
7 (0.65 g, 2.3 mmol) in CH2Cl2 (15 mL) and the resulting
mixture was stirred at rt overnight. The reaction mixture was
diluted with H2O, basified with 10% aqueous Na2CO3, and
extracted with CH2Cl2. The organic extracts were dried
and concentrated. Flash chromatography of the residue
(98:2 CH2Cl2–MeOH) gave the secondary amine (0.5 g).
This compound was dissolved in MeOH (16 mL) and treated
with (t-BuOCO)2O (0.57 g, 2.65 mmol) and Et3N (7.4 mL,
5.3 mmol). After the mixture was heated at reflux for 4 h,
the solvent was removed and the residue was diluted with
CH2Cl2 and washed with 1 N HCl and brine. The organic
extracts were dried and concentrated and the resulting resi-
due was chromatographed (flash, 95:5 hexanes–AcOEt) to
4.1.11. 3-[(N-Allyl-N-tert-butoxycarbonyl)aminomethyl]-
2-(1-hydroxy-2-propenyl)-1-(methoxymethyl)indole (12).
tert-BuLi (1.7 M in pentane, 0.87 mmol) was slowly added
under Ar to a solution of indole 11a (0.22 g, 0.72 mmol)
in anhydrous THF (10 mL) at ꢀ78 ꢁC, and the resulting
solution was stirred for 2 h at ꢀ78 ꢁC. Then, acrolein
(0.11 mL, 1.8 mmol) was added and the mixture was stirred
at ꢀ78 ꢁC for 3.5 h. The reaction mixture was poured into
10% aqueous NH4Cl and extracted with Et2O. The organic
extracts were dried and concentrated and the residue was
purified by flash chromatography (8:2 hexanes–AcOEt)
1
to give alcohol 12: 0.22 g (79%, unstable oil); H NMR
(gHSQC,) d 1.49 (s, 9H, 3CH3), 3.26 (s, 3H, OMe), 3.75
(m, 2H, NCH2CH]), 4.68 and 4.73 (2d, J¼15.3 Hz, 2H,
indCH2N), 5.09 (m, 1H, CH2]), 5.13 (m, 1H, CH2]),
5.24 (dm, J¼10.8 Hz, 1H, CH2]), 5.35 (dm, J¼17.0 Hz,
1H, CH2]), 5.47 and 5.62 (2d, J¼10.8 Hz, 2H, CH2OMe),
1
give 9a: 0.66 g (68%); H NMR d 1.48 (s, 9H), 3.70 (br s,

M.-L. Bennasar et al. / Tetrahedron 63 (2007) 861–866
865
5.72 (m, 2H, CHOH, CH]), 6.15 (m, 1H, CH]), 7.15 (m,
1H, ind 5-H), 7.24 (m, 1H, ind 6-H), 7.41 (d, J¼8.1 Hz, 1H,
ind 7-H), 7.68 (dm, J¼8.1 Hz, 1H, ind 4-H); 13C NMR d 28.5
(3CH3), 39.3 (CH2), 47.9 (CH2), 55.8 (CH3), 66.6 (CH),
74.5 (CH2), 80.0 (C), 109.5 (CH), 111.6 (C), 115.1 (CH2),
115.9 (CH2), 119.5 (CH), 120.5 (CH), 122.8 (CH), 128.0
(C), 134.0 (CH), 137.6 (C), 137.9 (C), 139.0 (CH), 155.7 (CO).
(d, J¼8.0 Hz, 1H, 8-H), 7.57 (d, J¼8.0 Hz, 1H, 11-H);
13C NMR (100.6 MHz, gHSQC, 1:1 mixture of rotamers)
d ꢀ4.6 (2CH3), 18.4 (C), 26.0 (3CH3), 28.7 and 28.8
(3CH3), 41.2 and 41.6 (C-1), 43.9 and 44.3 (C-3), 55.9
(OCH3), 66.4 and 66.5 (C-6), 75.2 and 75.4 (CH2O), 79.8
and 80.2 (C), 109.5 and 109.6 (C), 110.2 and 110.3 (C-8),
118.4 and 118.5 (C-11), 120.3 and 120.4 (C-10), 122.3 and
122.4 (C-9), 126.1 and 126.5 (C-5), 127.8 and 127.9 (C),
136.1 and 136.3 (C-4), 136.9 (C), 137.3 (C), 155.3 and
155.4 (CO); HRMS calcd for C26H40N2O4Si 472.2757,
found 472.2750.
4.1.12. 3-[(N-Allyl-N-tert-butoxycarbonyl)aminomethyl]-
2-[1-(tert-butyldimethylsilyloxy)-2-propenyl]-1-(methoxy-
methyl)indole (13). A solution of alcohol 12 (0.21 g,
0.5 mmol), TBDMSCl (0.25 g, 1.6 mmol), and imidazole
(0.15 g, 2.1 mmol) in DMF (3 mL) was heated under Ar
at 55 ꢁC overnight. The reaction mixture was partitioned
between 10% aqueous Na2CO3 and Et2O and extracted with
Et2O. The organic extracts were dried and concentrated. Flash
chromatography (9:1 hexanes–AcOEt) of the residue gave
4.1.15. 2-(tert-Butoxycarbonyl)-7-(methoxymethyl)-
6-oxo-1,2,3,6-tetrahydroazocino[4,3-b]indole (16). (Im)-
(PCy3)(Cl)2Ru]CHPh (second generation Grubbs catalyst,
10 mol %) was added under Ar to a solution of ketone 14
(25 mg, 0.065 mmol) in CH2Cl2 (2 mL) and the resulting
mixture was stirred at rt overnight. The reaction mixture was
filtered, the filtrate was concentrated, and the resulting resi-
due was purified by flash chromatography (8:2 hexanes–
1
13: 0.18 g (64%); IR (film) 1690; H NMR d 0.19 (s, 6H),
0.93 (s, 9H), 1.55 (s, 9H), 3.32 (s, 3H), 3.60 (br s, 2H), 4.77
(br s, 2H), 5.14 (m, 2H), 5.20 (dm, J¼9.0 Hz, 1H), 5.40 (d,
J¼15.0 Hz, 1H), 5.54 and 5.76 (2d, J¼10.0 Hz, 2H), 5.77
(m, 2H), 6.20 (m, 1H), 7.18 (m, 1H), 7.27 (m, 1H), 7.52 (d,
J¼7.8 Hz, 1H), 7.68 (d, J¼7.8 Hz, 1H); 13C NMR d ꢀ4.6
(2CH3), 18.6 (C), 26.1 (3CH3), 28.8 (3CH3), 38.7 (CH2),
47.3 (CH2), 56.0 (CH3), 68.1 (CH), 75.8 (CH2), 80.0 (C),
109.9 (C), 110.8 (CH), 114.6 (CH2), 116.0 (CH2), 119.5
(CH), 120.6 (CH), 122.8 (CH), 128.4 (C), 134.1 (CH),
137.6 (CH), 138.3 (C), 139.9 (C), 155.8 (CO); HRMS calcd
for C28H44N2O4Si 500.3070, found 500.3062.
1
AcOEt) to give 16: 20 mg (86%); H NMR (400 MHz)
d 1.48 (br s, 9H), 3.27 (s, 3H), 3.91 (br s, 2H), 4.83 (s,
2H), 5.99 (s, 2H), 6.44 (m, 1H), 6.63 (d, J¼11.7 Hz, 1H),
7.26 (m, 1H), 7.43 (m, 1H), 7.55 (d, J¼8.4 Hz, 1H), 7.90
(m, 1H); 13C NMR (100.6 MHz) d 28.8 (3CH3), 37.2
(CH2), 39.6 (CH2), 56.3 (CH3), 75.4 (CH2), 81.1 (C),
111.6 (CH), 121.4 (CH, C), 122.0 (CH), 126.5 (C), 127.6
(CH), 133.7 (C), 135.7 (CH), 138.4 (C), 139.9 (CH), 154.6
(CO), 184.2 (CO). Anal. Calcd for C20H24N2O4$1/2H2O:
C, 65.74%; H, 6.90%; N, 7.67%. Found: C, 65.85%; H,
6.66%; N, 7.65%.
4.1.13. 3-[(N-Allyl-N-tert-butoxycarbonyl)aminomethyl]-
1-(methoxymethyl)-2-propenoylindole (14). Alcohol 12
(39 mg, 0.1 mmol) and MnO2 (87 mg, 1.0 mmol) in CH2Cl2
(6 mL) were stirred at rt for 60 h. The reaction mixture was
filtered through Celite and the filtrate was concentrated. The
resulting residue was purified by flash chromatography (8:2
hexanes–AcOEt) to give ketone 14: 25 mg (64%); 1H NMR
d 1.50 (s, 9H), 3.19 (s, 3H), 3.55 (br s, 2H), 4.86 (s, 2H), 4.90
(dm, J¼15.0 Hz, 1H), 5.05 (dm, J¼9.6 Hz, 1H), 5.60 (br s,
1H), 5.64 (s, 2H), 5.99 (dd, J¼10.5, 1.5 Hz, 1H), 6.30 (dd,
J¼17.1, 1.5 Hz, 1H), 6.89 (dd, J¼17.1, 10.5 Hz, 1H), 7.22
(m, 1H), 7.40 (m, 1H), 7.50 (d, J¼7.8 Hz, 1H), 7.80 (br d,
J¼7.8 Hz, 1H); 13C NMR d 28.7 (3CH3), 40.0 (CH2), 47.5
(CH2), 56.3 (CH3), 75.4 (CH2), 80.0 (C), 111.1 (CH),
116.6 (CH2), 119.4 (C), 121.8 (CH), 122.2 (CH), 126.2
(CH), 127.3 (C), 131.2 (CH2), 133.8 (CH), 135.2 (C),
137.3 (CH), 138.9 (C), 155.8 (CO), 187.7 (CO); HRMS
calcd for C22H28N2O4 384.2049, found 384.2033.
4.1.16. 2-(tert-Butoxycarbonyl)-6-(tert-butyldimethyl-
silyloxy)-7-(methoxymethyl)-1,2,3,4,5,6-hexahydroazo-
cino[4,3-b]indole (17). Compound 15 (63 mg, 0.13 mmol)
dissolved in MeOH (6 mL) was hydrogenated over Pd/C
(5%, 3.5 mg) for 12 h. The catalyst was filtered, the filtrate
was concentrated, and the resulting residue was purified
by flash chromatography (8:2 hexanes–AcOEt) to give azo-
cinoindole 17: 51 mg (80%); 1H NMR (400 MHz) d 0.08 (s,
3H), 0.93 (s, 9H), 1.46 and 1.55 (2s, 9H), 1.8 (m, 2H), 2.15
(m, 1H), 2.90 (m, 1H), 3.23 (s, 3H), 3.50 and 3.85 (2m, 2H),
4.85 (m, 2H), 5.51 (m, 1H), 5.56 and 5.68 (2d, J¼14.4 Hz,
2H), 7.10–7.26 (m, 2H), 7.42 (d, J¼8.0 Hz, 1H), 7.75 (m,
1H); 13C NMR (1:1 mixture of rotamers) d ꢀ4.64 (2CH3),
18.5 (C), 24.0 and 24.1 (CH2), 26.2 (3CH3), 29.0 (3CH3),
36.9 and 37.3 (CH2), 39.4 and 39.7 (CH2), 43.9 and 44.2
(CH2), 56.0 (CH3), 67.4 (CH), 74.6 (CH2), 79.9 (C), 109.5
and 109.7 (CH), 110.4 and 110.5 (C), 119.1 and 119.5
(CH), 120.3 and 120.5 (CH), 122.4 (CH), 127.99 and
128.5 (C), 137.5 (C), 139.5 (C), 155.4 (CO); HRMS calcd
for C26H42N2O4Si 474.7083, found 474.7078.
4.1.14. 2-(tert-Butoxycarbonyl)-6-(tert-butyldimethyl-
silyloxy)-7-(methoxymethyl)-1,2,3,6-tetrahydroazo-
cino[4,3-b]indole (15). Diene 13 (0.17 g, 0.33 mmol) was
allowed to react with (PCy3)2(Cl)2Ru]CHPh (10 mol %)
in CH2Cl2 (9 mL) as described in Section 4.1.4. After
work-up and flash chromatography (95:5 hexanes–AcOEt),
compound 15 was obtained: 0.135 g (85%); 1H NMR
(400 MHz, gHSQC, 1:1 mixture of rotamers) d 0.07 (s,
6H, CH3), 0.91 (s, 9H, CH3), 1.46 and 1.49 (2s, 9H, CH3),
3.18 (s, 3H, OCH3), 3.50, 3.75, and 3.96 (3m, 2H, 3-H),
4.52, 4.68, 4.87, and 5.10 (4d, J¼16.0 Hz, 2H, 1-H), 5.45
and 5.63 (2m, 1H, 5-H), 5.63 and 5.83 (2m, 2H, OCH2),
5.91 and 6.03 (2m, 1H, 4-H), 6.18 (br s, 1H, 6-H), 7.16
(t, J¼8.0 Hz, 1H, 10-H), 7.21 (t, J¼8.0 Hz, 1H, 9-H), 7.45
4.1.17. 2-(tert-Butoxycarbonyl)-6-oxo-7-(methoxy-
methyl)-1,2,3,4,5,6-hexahydroazocino[4,3-b]indole (18).
Operating as above, from 16 (0.28 g, 0.78 mmol) azocino-
indole 18 was obtained after flash chromatography (6:4
1
hexanes–AcOEt): 0.23 g (82%); H NMR (1:1 mixture of
rotamers) 1.19 and 1.45 (2s, 9H), 2.10 (br, 2H), 2.95 (br,
2H), 3.21 (s, 3H), 3.55 and 3.65 (2m, 2H), 4.80 and 4.90
(2br s, 2H), 5.73 (br, 2H), 7.20 (t, J¼8.0 Hz, 1H), 7.38 (t,
J¼8.0 Hz, 1H), 7.50 (br d, J¼8.0 Hz, 1H), 7.70 (m, 1H);
13C NMR (1:1 mixture of rotamers) 25.3 and 25.6 (CH2),

866
M.-L. Bennasar et al. / Tetrahedron 63 (2007) 861–866
5. For specific examples of enyne RCM, see: (a) Schramm, M.-P.;
Reddy, D. S.; Kozmin, S. A. Angew. Chem., Int. Ed. 2001,
28.2 and 28.3 (3CH3), 41.7 and 41.9 (CH2), 43.4 and 44.1
(CH2), 46.1 and 47.9 (CH2), 55.8 (CH3), 74.7 (CH2), 80.0
(C), 110.7 and 110.9 (CH), 120.2 and 120.5 (CH), 121.3
and 121.4 (CH), 122.3 (C), 125.8 and 126.0 (CH, C),
132.5 (C), 137.8 (C), 155.4 (CO), 197.6 and 198.2 (CO);
HRMS calcd for C20H26N2O4 358.1892, found 358.1887.
ꢀ
49, 4274–4277; (b) Perez-Serrano, L.; Casarrubios, L.;
Domınguez, G.; Freire, G.; Perez-Castells, J. Tetrahedron
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2002, 58, 5407–5415; (c) Gonzalez-Gomez, A.; Domınguez,
G.; Perez-Castells, J. Tetrahedron Lett. 2005, 46, 7267–7270.
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6. (a) Sundberg, R. J. Indoles; Academic: New York, NY, 1996;
(b) Joule, J. A. Science of Synthesis (Houben–Weyl, Methods
of Molecular Transformations); Georg Thieme: Stuttgart,
2000; Vol. 10, pp 361–652; (c) Somei, M.; Yamada, F. Nat.
Prod. Rep. 2005, 22, 73–103 and 761–793.
Acknowledgements
Financial support from the ‘Ministerio de Ciencia y
7. Joule, J. A. Indoles, The Monoterpenoid Indole Alkaloids;
Saxton, J. E., Ed.; Wiley: New York, NY, 1983; Vol. 25,
pp 265–292.
ꢀ
Tecnologıa’ (MCYT-FEDER, Spain) through project
BQU2003-04967-C-02-02 is gratefully acknowledged.
8. For pioneering synthetic approaches to apparicine, see: Joule,
J. A.; Allen, M. S.; Bishop, D. I.; Harris, M.; Hignett, G. J.;
Scopes, D. I. C.; Wilson, N. D. V. Indole and Biogenetically
Related Alkaloids; Phillipson, J. D., Zenk, M. H., Eds.;
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