A synthetic entry to 2,3-fused ring indole derivatives by ring-closing metathesis reactions

Article abstract of DOI:10.1016/j.tetlet.2004.06.097

a- a- a- Six to eight-membered carbocycles and eight-membered azacycles fused to the 2,3-position of the indole ring, representing tricyclic substructures of several indole alkaloids, can be synthesized by RCM reactions from easily accessible dienic precu

Full text of DOI:10.1016/j.tetlet.2004.06.097

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6283–6285
A synthetic entry to 2,3-fused ring indole derivatives by
ring-closing metathesis reactions
M.-Llu¨ısa Bennasar,* Ester Zulaica and Sven Tummers
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, Barcelona 08028, Spain
Received 25 March 2004; revised 14 June 2004; accepted 22 June 2004
Abstract—Six to eight-membered carbocycles and eight-membered azacycles fused to the 2,3-position of the indole ring, represent-
ing tricyclic substructures of several indole alkaloids, can be synthesized by RCM reactions from easily accessible dienic precursors.
Ó 2004 Elsevier Ltd. All rights reserved.
Ring-closing metathesis (RCM) reactions1 have become
n
increasingly important in organic synthesis, and are now
well-established processes for the construction of a great
variety of carbo and heterocyclic systems.2 In this con-
text, considerable effort has been recently directed to
the synthesis of benzo fused bicyclic compounds,1,2
including quinolines,3 chromenes4 or larger rings.5 How-
ever, there are relatively few examples that make use of
RCM reactions for the synthesis of analogous indole
derivatives,6 a prominent class of heterocyclic systems
found in many natural and medicinal compounds.7
Our interest in the chemistry of indoles8 led us to envis-
age RCM reactions as a useful tool for the construction
of indole 2,3-fused carbo and azacycles,9 which consti-
tute structural arrangements present in some indole
alkaloids such as ervitsine10 or apparicine11 (Scheme
1). In this Letter we report our preliminary results con-
cerning this annulation procedure using easily accessible
indole-containing diene precursors.
n
catalyst
n = 1-3
N
N
R
R
Me
N
N
D
C
D
C
A
B
B
A
N
CH2
H
N
O
H
Ervitsine
Apparicine
Scheme 1.
with vinylmagnesium bromide. However, this com-
pound appeared to be very unstable and decomposed
under chromatographic purification conditions. As this
behaviour was probably associated with the presence
of a 3-indolylmethanol moiety, we decided to place a
strong electron-withdrawing group such as the benz-
enesulfonyl at the nitrogen of the starting allylindole
1b.14 Satisfactorily, Friedel–Crafts reaction with dichlo-
romethyl methyl ether in the presence of TiCl4 gave
aldehyde 2b (90% yield), which upon exposure to vinyl,
allyl or 3-butenyl-magnesium bromide gave the stable
RCM precursors 3b, 4 and 5, respectively, in 75–85%
yield.
We planned to examine the feasibility of the RCM pro-
tocol in the carbocyclic series using 2-allylindoles (e.g.,
3–5, Scheme 2), which incorporate hydroxyalkenyl
chains of different lengths at the 3-position. A similar
approach had been used for the synthesis of 1,2-fused
ring indole derivatives.6c Initially, we focused our atten-
tion on N-methyl derivative 3a, which was prepared in
60% overall yield from the known 2-allylindole 1a,12
by Vilsmeier reaction with oxalyl chloride and DMF,
followed by treatment of the resulting aldehyde 2a13
Considering the substitution pattern of dienes 3b, 4 and
5, their RCM reactions were next attempted using the
commercially available ruthenium carbene catalyst
(PCy3)2(Cl)2Ru@CHPh (first generation Grubbs cata-
lyst, Scheme 3). Ring closure of diene 3b took place at
Keywords: Ring-closing metathesis; Indoles; Indole alkaloids.
*
Corresponding author. Tel.: +34-9340-24540; fax: +34-9340-
24539; e-mail: bennasar@ub.edu
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.097

6284
M.-L. Bennasar et al. / Tetrahedron Letters 45 (2004) 6283–6285
CHO
b
a
a
CHO
SO Ph
N
N
N
SO Ph
N
R
R
1
2
2
2
11
10
a. R = Me
b
c
b. R = SO Ph
2
HO
c
HO
N
OH
N
N
n
OH
SO Ph
SO Ph
2
2
12
13
N
Scheme 3. Reagents and conditions: (a) t-BuLi, THF, À78°C, 30min,
then, DMF, À78°C to rt, 60%; (b) BrMgCH2CH@CH2, THF, À78°C
to 0°C, 3h, 86%; (c) 10mol% (PCy3)2(Cl)2Ru@CHPh, CH2Cl2, reflux,
overnight, 60%.
R
3
4 n = 1
5 n = 2
SO Ph
2
d
e
n
HO
N
The above success in the carbocyclic series, in particular
the efficient construction of the eight-membered carbo-
cycle 8, led us to study RCM reactions from similar die-
nes incorporating a nitrogen in the tether linking the two
olefinic moieties. Starting from aldehyde 2b, a rapid ac-
cess to the ABC ring substructure of apparicine through
diallyl derivatives 15 or 16, bearing different protecting
groups at the aliphatic nitrogen, was envisaged (Scheme
4). Thus, reductive amination of 2b with allylamine un-
der mild conditions, followed by reaction of the result-
ing secondary amine 14 with di-tert-butyl carbonate
gave carbamate 15, which underwent cyclization under
the above RCM conditions to give the azocino[4,3-b]in-
dole 17 in 60% yield. As expected considering the
precedents for RCM reactions from nitrogen comp-
ounds,2 the N-tosyl derivative 16, prepared by sulfonyla-
tion of 14, was a better substrate as it led to 1819 in a
higher yield (89%).
SO Ph
6
2
N
HO
SO Ph
2
7 n = 1
8 n = 2
N
SO Ph
2
9
Scheme 2. Reagents and conditions: (a) For 2a: (COCl)2, DMF,
CH2Cl2, rt, 8h, 75%; for 2b: Cl2CHOMe, TiCl4, CH2Cl2, À78°C, 3h,
90%; (b) BrMgCH@CH2, THF, À78°C to 0°C, 3h, 80% (3a, crude
product), 75% (3b); (c) BrMg(CH2)nCH@CH2, THF, À78°C to 0°C,
3h, 82% (4), 85% (5); (d) 5mol% (PCy3)2(Cl)2Ru@CHPh, CH2Cl2, rt,
62%; (e) 10mol% (PCy3)2(Cl)2Ru@CHPh, CH2Cl2, reflux, overnight,
65% (7+9), 85% (8).
room temperature in dichloromethane to give the fully
aromatic carbazole 6 (62% yield), coming from an addi-
tional in situ dehydration step. As anticipated, cycliza-
tions of the higher homologous dienes 4 and 5 were a
bit slower and they were better performed in refluxing
dichloromethane. Under these conditions, 4 gave a mix-
ture (variable ratio, 65% yield) of the expected cyclohep-
ta[b]indole 7 and its isomer 9, in which the double bond
has moved to the indole a-position. The above isomeri-
zation to a 2-vinylindole system deserves comment as it
might be mediated by the Grubbs catalyst or some spe-
cies derived from it,15,16 although a more conventional
route cannot be discarded. In contrast, no isomerization
was observed from 5, which gave cycloocta[b]indole 817
as the only product in the highest yield in this series
(85%).
General experimental procedure: The ruthenium catalyst
(10mol%) was added under argon to a solution of the
appropriate diene (4, 5, 12, 15 or 16) in anhydrous
CH2Cl2 (c 0.033M), and the resulting mixture was ref-
luxed overnight. The solvent was removed and the
resulting residue was purified by flash chromatography
(SiO2, hexanes and hexanes–AcOEt) to give the corre-
sponding tricyclic compounds.
In conclusion, we have described a synthetic approach
to a range of 2,3-fused ring indole derivatives from sim-
R
R
N
N
As depicted in Scheme 3, it was also possible to synthe-
size isomeric fused tricyclic indoles, for example, cyclo-
hepta[b]indole 13, through a similar synthetic sequence
starting from 3-allylindole 10.14 In our hands, it was
not possible to introduce the required formyl group by
a Friedel–Crafts reaction but aldehyde 11 could be ob-
tained in 60% yield by treatment of the 2-lithio deriva-
tive of 10 with DMF.18 Reaction of aldehyde 11 with
allylmagnesium bromide gave 12 (86% yield), which
was submitted to the above RCM conditions to give
13 as the only product in 60% yield, again with no trace
of isomerization product.
d
a
2b
N
N
SO Ph
SO Ph
2
2
17 R = Boc
18 R = Ts
14 R = H
15 R = Boc
16 R = Ts
b
c
Scheme 4. Reagents and conditions: (a) allylamine, AcOH, NaB-
H(OAc)3, rt, overnight, 85%; (b) (t-BuO)2CO, 4:1 MeOH–triethylam-
ine, reflux, 4h, 75%; (c) TsCl, Et3N, CH2Cl2, rt, overnight, 70%; (d)
10mol% (PCy3)2(Cl)2Ru@CHPh, CH2Cl2, reflux, overnight, 60% (17),
89% (18).

M.-L. Bennasar et al. / Tetrahedron Letters 45 (2004) 6283–6285
6285
Griera, J.; Bassa, M.; Bosch, J. J. Org. Chem. 2002, 67,
6268–6271; (c) Bennasar, M.-L.; Roca, T.; Ferrando, F.
Org. Lett. 2004, 6, 759–762.
ple precursors, using the Grubbs catalyst in the key ring-
closing step. The extension of this work to the synthesis
of indole alkaloids and related structures is currently un-
der investigation.
9. For a previous use of RCM for the construction of 2,3-
fused ring indoles, see: (a) Selvakumar, N.; Khera, M. K.;
Reddy, B. Y.; Srinivas, D.; Azhagan, A. M.; Iqbal, J.
Tetrahedron Lett. 2003, 44, 7071–7074; (b) Yang, X.;
Althammer, A.; Knochel, P. Org. Lett. 2004, 6,
1665–1667, See also Ref. 6d.
Acknowledgements
Financial support from the ÔMinisterio de Ciencia y Tec-
10. For synthesis of alkaloids of the ervitsine-ervatamine
group, see: (a) Bennasar, M.-L.; Vidal, B.; Bosch, J. J.
Org. Chem. 1997, 62, 3597–3609; (b) Bennasar, M.-L.;
´
nologıaÕ, Spain, and the ÔFondo Europeo de Desarrollo
RegionalÕ (FEDER) through project BQU2003-04967-
C02-02 is gratefully acknowledged. We also thank the
DURSI (Generalitat de Catalunya) for Grant
2001SGR00084.
´
Vidal, B.; Kumar, R.; Lazaro, A.; Bosch, J. Eur. J. Org.
Chem., 2000, 3919–3925; (c) Bennasar, M.-L.; Zulaica, E.;
Alonso, Y.; Bosch, J. Tetrahedron: Asymmetry 2003, 14,
469–479.
11. Joule, J. A. In Indoles, The Monoterpenoid Indole Alka-
loids; Saxton, J. E., Ed.; In The Chemistry of Heterocyclic
Compounds; Weissberger, A., Taylor, E. C., Eds.; Wiley:
New York, 1983; Vol. 25, Part 4, Chapter VI.
References and notes
1. (a) Grubbs, R. H., Ed. Handbook of Metathesis; Wiley–
VCH: Weinheim, 2003; Vol. 2; For selected reviews, see:
(b) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54,
12. Ishikura, M.; Terashima, M. J. Chem. Soc., Chem.
Commun. 1989, 727–728.
13. All new compounds gave analytical and spectral data
consistent with the proposed structures.
4413–4450; (c) Furstner, A. Angew. Chem., Int. Ed. 2000,
¨
39, 3012–3043; (d) Hoveyda, A. H.; Schrock, R. R. Chem.
Eur. J. 2001, 7, 945–950.
14. Kondo, Y.; Takazawa, N.; Yoshida, A.; Sakamoto, T.
J. Chem. Soc., Perkin Trans. 1, 1995, 1207–1208.
15. It has been reported that alkene isomerizations sometimes
interfere with the desired metathesis process. For discus-
sions, see: (a) Alcaide, B.; Almendros, P. Chem. Eur. J.
2003, 9, 1259–1262; (b) Schmidt, B. Angew. Chem., Int.
Ed. 2003, 42, 4996–4999.
2. For recent reviews on the application of RCM to the
synthesis of heterocycles, see: (a) Walters, M. A., Gribble,
G. W., Joule, J. A., Eds.; Progress in Heterocyclic
Chemistry; Pergamon: Amsterdam, 2003; Vol. 15, pp
1–36; (b) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 5,
2199–2238.
16. Useful RCM-alkene isomerization sequences have been
recently described, the latter process being promoted by in
situ modified ruthenium catalysts: (a) Sutton, A. E.;
Seigal, B. A.; Finnegan, D. F.; Snapper, M. L. J. Am.
Chem. Soc. 2002, 124, 13390–13391; (b) Schmidt, B. Eur.
J. Org. Chem. 2003, 5, 816–819; (c) Schmidt, B. Chem.
Commun. 2004, 742–743.
3. (a) Theeraladanon, C.; Arisawa, M.; Nishida, A.; Naka-
gawa, M. Tetrahedron 2004, 60, 3017–3035; (b) Rosillo,
´
M.; Domınguez, G.; Casarrubios, L.; Amador, U.; Perez-
Castells, J. J. Org. Chem. 2004, 69, 2084–2093.
´
4. For instance, see: (a) Chang, S.; Grubbs, R. H. J. Org.
Chem. 1998, 63, 864–866; (b) van Otterlo, W. A. L.; Ngidi,
E. L.; Coyanis, E. M.; de Koning, C. B. Tetrahedron Lett.
2003, 44, 311–313; (c) Hardouin, C.; Burgaud, L.; Valleix,
A.; Doris, E. Tetrahedron Lett. 2003, 44, 435–437.
5. For instance, see: (a) Lane, C.; Snieckus, V. Synlett, 2000,
1294–1296; (b) van Otterlo, W. A. L.; Pathak, R.; de
Koning, C. B. Synlett, 2003, 1859–1861; (c) Dolman, S. J.;
Schrock, R. R.; Hoveyda, A. H. Org. Lett. 2003, 5,
4899–4902.
17. Selected spectroscopic data for 8: IR (film) 3417cmÀ1
1
(OH); H NMR (CDCl3, 300MHz): d 1.98 (m, 4H), 3.68
(dd, J=18 and 6Hz, 1H, 6-H), 4.25 (dd, J=18 and 6.3Hz,
1H, 6-H), 5.35 (m, 1H, 11-H), 5.60 (m, 1H, @CH), 5.73
(m, 1H, @CH), 7.18–7.58 (m, 6H), 7.70 (m, 2H), 8.20 (m,
1H, 4-H); 13C NMR (CDCl3, 75.4MHz): d 22.6 (CH2),
26.1 (CH2), 32.5 (CH2), 67.8 (CH), 115.0 (CH), 119.6
(CH), 122.2 (C), 123.4 (CH), 124.1 (CH), 126.6 (C), 126.2
(2CH), 129.1 (2CH), 128.9 (CH), 129.9 (CH), 133.6 (CH),
133.8 (C), 136.5 (C), 138.9 (C).
6. 1,2-Fused rings: (a) Birman, V. B.; Rawal, V. H. J. Org.
Chem. 1998, 63, 9146–9147; (b) Schramm, M.-P.; Reddy,
D. S.; Kozmin, S. A. Angew. Chem., Int. Ed. 2001, 49,
18. Gribble, G. W.; Jiang, J.; Liu, Y. J. Org. Chem. 2002, 67,
1001–1003.
´
´
´
4274–4277; (c) Gonzalez-Perez, P.; Perez-Serrano, L.;
Casarrubios, L.; Domınguez, G.; Perez-Castells, J. Tetra-
´
19. Selected spectroscopic data for 18: 1H NMR (CDCl3,
300MHz, 1H COSY): d 2.40 (s, 3H, Me), 3.76 (d, J=
6.6Hz, 2H, 3-H), 3.98 (d, J=6.9Hz, 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,
12-H, Ar), 8.20 (d, J=7Hz, 1H, 8-H); 13C NMR (CDCl3,
75.4MHz, 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 (C), 136.4 (C), 138.8 (C), 143.3
(C).
´
`
hedron Lett. 2002, 43, 4765–4767; (d) Chacun-Lefevre, L.;
Beneteau, V.; Joseph, B.; Merour, J.-Y. Tetrahedron 2002,
´ ´
´
´
58, 10181–10188; 3,4-Fused carbocyclic rings: (e) Perez-
Serrano, L.; Casarrubios, L.; Domınguez, G.; Freire, G.;
´
´
Perez-Castells, J. Tetrahedron 2002, 58, 5407–5415; 3,4-
Fused azacyclic systems: (f) Kalinin, A.; Chauder, B. A.;
Rahkit, S.; Snieckus, V. Org. Lett. 2003, 5, 3519–3521.
7. Sundberg, R. J. Indoles; Academic: New York, 1996.
8. (a) Bennasar, M.-L.; Roca, T.; Griera, R.; Bosch, J. Org.
Lett. 2001, 3, 1697–1700; (b) Bennasar, M.-L.; Roca, T.;