Enyne and dienyne metathesis reactions in β-carbolines

Article abstract of DOI:10.1016/j.tetlet.2005.07.140

New indolic enynes and dienynes, based on the β-carboline system, give metathesis products with ruthenium catalysts. The synthesis of the starting materials is readily achieved from tryptamine. The tuning up of the conditions for the metathesis is discussed. Cascade metathesis gives an oxidized pentacyclic product.

Full text of DOI:10.1016/j.tetlet.2005.07.140

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7267–7270
Enyne and dienyne metathesis reactions in b-carbolines
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*
´
´
´
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Alvaro Gonzalez-Gomez, Gema Domınguez and Javier Perez Castells
Departamento de Quı´mica, Facultad de Farmacia, Universidad San Pablo-CEU, Urb. Monteprı´ncipe,
Boadilla del Monte, 28668 Madrid, Spain
Received 24 June 2005; revised 27 July 2005; accepted 27 July 2005
Available online 6 September 2005
Abstract—New indolic enynes and dienynes, based on the b-carboline system, give metathesis products with ruthenium catalysts.
The synthesis of the starting materials is readily achieved from tryptamine. The tuning up of the conditions for the metathesis is
discussed. Cascade metathesis gives an oxidized pentacyclic product.
Ó 2005 Elsevier Ltd. All rights reserved.
The enyne metathesis reaction1 is completely atom eco-
H
N
N
nomical and formally implies the formation of a car-
bon–carbon bond and the migration of the alkylidene
part onto the alkyne carbon, to form a diene. In recent
years, there has been great interest in intramolecular en-
yne metathesis2 especially with regard to further trans-
formations of the resulting conjugated dienes. Thus,
domino transformations, including tandem RCM of
dienynes,3 have lead to synthetic applications in the field
of polycycle construction and natural product syntheses.
N
N
H
H
HO
MeOOC
CH3
MeOOC
OH
Vincamine
N
Geissoschizine
N
NCH3
H
Br
N
H
Enynes connected through an aromatic ring are interest-
ing substrates that have found scarce use in this chemis-
try. We have used benzenic and indolic enynes to
construct complex polycycles.4 In this paper, we describe
the first use of b-carboline derived enynes and dienynes
in metathesis processes involving tandem metathesis
reactions.
O
CH3
Homoeburnane
Arborescidine B
Figure 1. Some b-carboline alkaloids.
products can be made selectively (Scheme 1). Thus,
excess of base and allyl bromide gave 4 as the only reac-
tion product in 65% yield, while the use of 1 equiv of
base and 2 equiv of allyl bromide gave a 2:1 mixture
of 2 and 3 which was separated by column chromato-
graphy, yielding pure 2 (64%) and 3 (30%). Compound
3 was protected on the indole nitrogen with tosyl chlo-
ride using NaH as the base, giving 5 in 80% yield.
This new approach is a powerful entry into polycyclic
structures related to alkaloids containing the b-carboline
unit such as those depicted in Figure 1.
The synthesis of the starting enynes was accomplished
from tryptamine. The reaction of tryptamine with ethyl-
formate gives formamide 1 which, when treated with
NaH and allyl bromide gives a mixture of monoallyl
derivatives 2 and 3 and diallylcompound 4. With a care-
ful selection of the reaction conditions mono- or diallyl
Compound 2 was cyclized using the Bischler–Napieral-
ski reaction, giving the corresponding 9-allyldihydro-b-
carboline which was reacted with an alkynylmagnesium
bromide and protected, to afford the desired enynes
6a,b. Best yields were achieved when isolating the inter-
mediate cyclic imine (Scheme 2a). On the other hand,
compounds 4 and 5, were reacted with POCl3 and the
Keywords: Enynes; b-Carboline; Metathesis; Cascade reactions;
Ruthenium.
*
Corresponding author. Tel.: +34 913724700; fax: +34 913510475;
e-mail: jpercas@ceu.es
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.140

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A. Gonza´lez-Go´mez et al. / Tetrahedron Letters 46 (2005) 7267–7270
7268
than dichloromethane (entries 2 and 3). All reactions
NCHO
R2
NHCHO
NaH
were carried out at room temperature, as extensive
decomposition of the starting material occurred when
operating at an elevated temperature.
N
R1
N
H
Br
2-5
1
We used a 10 mol% catalyst because we observed a sig-
nificant decrease in yield when using only 5% of catalyst
(entry 4). This point may be surprising as it is thought
that complex B generates small amounts of 14eÀ active
species that give a high number of catalytic cycles.5
Our reactions were at that point very slow and needed
3 days to complete. We have monitorized the RCM of
6a–10a by 1H NMR which indicated the progressive
conversion of the starting material into the diene.6 In
this context, the need for such a high amount of catalyst
might be due to its partial decomposition. We have
observed similar yields when adding the catalysts in
portions every 12 h (3% at the beginning and 1%
additional every 12 h, completing 8%). We used
10 mol% of complex C, yielding 55% of 10a although
this reaction needed 6 days to complete (entry 5). In
view of these results, cheaper complex B was used for
the rest of the metathesis reactions. Our results im-
proved remarkably when performing the reaction under
an ethylene atmosphere (entry 6).7 Ethylene is known to
have a beneficial effect in metathesis reactions.8 This
conditions allowed the synthesis of 10a in only 3 h, using
5% of catalysts and in 95% yield.
R1
R2 Prod. Yield Conditionsa
H
Allyl
H
2
3
4
5
64%
30%
65%
80%
1:1:2
1:1:2
1:5:5
Allyl
Allyl
Allyl
NaH
p-TsCl
Allyl
Ts
a Proportion of indole:base:allylbromide.
Scheme 1. Synthesis of enyne precursors.
corresponding Grignard reagent in a Ôone-potÕ fashion,
affording 7 and 8a,b, respectively, in good yields
(Scheme 2c and d). In this approach the synthesis of
8a,b started from 3 which was a minor product obtained
in the alkylation of 1. As the yield of compound 3 was
low, an alternative synthesis of 8a,b was addressed.
Thus, we transformed quantitatively formamide 1 into
the corresponding dihydro-b-carboline which was pro-
tected as the tosyl derivative, using in this case
Cs2CO3/K2CO3 as the base. The reaction with the
appropriate alkynylmagnesium bromide yielded 9a,b in
52–59% yield from 1 (Scheme 2b). Subsequent allylation
of these intermediates in position 2 gave 8a,b. The global
yield of this route from 1 to the enynes 8a,b is 42% and
49%, respectively.
In the same way compound 6b was readily transformed
into diene 10b. The use of ethylene allowed raising the
yield to 85% (Scheme 3, entries 7 and 8).
We accomplished next, the metathesis reaction of these
starting compounds. The reaction of enyne 6a was used
as a model and was reacted with catalysts A, B and C
under different reaction conditions (Scheme 3). While
catalyst A did not give any conversion (entry 1), both
complexes B and C led to the desired diene product
10a with similar yields, toluene being a better solvent
We also used these reaction conditions to carry out the
metathesis reactions of 8a,b. These substrates gave the
corresponding dienes 11 in good yield along with small
amounts of an oxidized pyrrole 12. This ability to oxi-
dize the reaction product is a known non-metathetic
behaviour of ruthenium catalysts and it is particularly
observed with complexes of type B (Scheme 4).9
1, 2
POCl3
1) Cs2CO3/K2CO3
p-TsCl
BrMg
R
1)
N Ts
R
N H
R
2)
BrMg
R
BF3*Et2O
N
(a)
(b)
N
N
Ts
N
Z
2) NaH, p-TsCl
BF3*Et2O
Z = Allyl
Z = H
R = H, 52%
R = H, 58%
9a-b
6a-b
R = Me, 59%
R = Me, 56%
NaH,
Br
81-83%
NCHO
1) POCl3
2)
1) POCl3
N
(c)
N
(d)
N
Ts
N
2)
BrMg
R
N
Z
BrMg
Z = Ts
R
Z = Allyl
75%
R
R = H, 67%
8a-b
4, 5
R = Me, 55%
7
Scheme 2. Synthesis of starting enynes and dienynes.

´
A. Gonza´lez-Go´mez et al. / Tetrahedron Letters 46 (2005) 7267–7270
7269
Cat
toluene, RT
N
N
Ts
Ts
R
N
N
R
10a-b
Cat.
6a-b
Time Prod. Yield(%)
Solv.
No.
R
Mes
N
N Mes
1
2
3
4
5
6
7
8
H
H
H
H
H
H
A, 10% DCM
B, 10% DCM
B, 10% Tol.
B, 5% Tol.
C, 10% Tol.
B, 5% Tol.
10a
10a
10a
10a
10a
10a
10b
10b
5d
3d
3d
3d
6d
3ha
3d
3ha
-
Mes
N
N Mes
Ph
PCy3
Ru
PCy3
45
60
52
55
95
72
85
Cl
Cl
Cl
Ph
Cl
Ru
O
Cl
Ru
Cl
PCy3
A
B
C
Me B, 10% Tol.
Me B, 5% Tol.
a Performed under a 1 atm of ethylene.
Scheme 3. Metathesis reaction and tandem metathesis-Diels–Alder reaction of compounds 6a,b.
found no improvement by working under an ethylene
atmosphere.10
N
N
Cat B,
+
8a-b
N
Ts
N
Ts
10%
In conclusion, we show here the first enyne metathesis
reactions in b-carbolines leading to polycyclic systems
related to alkaloids. The synthesis of natural products
using this methodology is currently underway.
R
R
12a, 9%
11a, 62%
11b, 51%
12b, traces
Acknowledgements
N
N
7
N
N
The authors are grateful to the DGES (MEC-Spain,
Grant BQU2002-00137), the Universidad San Pablo-
CEU (Grant 07/03) for financial support. A.G.-G.
acknowledges the Spanish MEC for a pre-doctoral
fellowship.
13, not detected
14, not detected
Cat., %
Time Temp.Yield
N
-
A, 10%
B, 10%
B, 6%a
C, 6%a
5d
5d
r.t.
r.t.
N
Supplementary data
15%
45%
67%
3d 80 oC
3d 80 oC
Supplementary data associated with this article can be
found, in the online version at doi:10.1016/j.tetlet.
2005.07.140. Experimental procedures and full spectro-
scopical data for all new compounds.
15
a 2 mol% added every 24 h.
Scheme 4. Metathesis of 8a,b and cascade metathesis of 7.
Finally, we present the first example of a tandem
metathesis reaction on a b-carboline derivative. When
reacting compound 7 under the above conditions we iso-
lated in low yield a new pentacyclic structure whose
analytical and spectroscopical data corresponded to
compound 15. The cascade metathesis of compound 7
starts by reaction of one of the double bonds with the
ruthenium carbene. The formation of 15 implies the
coordination of the ruthenium first with the allyl group
in position 9 of the starting material to give 14 which is
oxidized under the reaction medium to 15. Reaction
with the allyl group in first would have produced 13
which was not detected in any of the reactions. In addi-
tion, raising the reaction temperature to 80 °C gave bet-
ter yields of 15. Thus, we switched to catalyst C, a more
stable complex towards heat, and 2% catalyst was added
to the reaction every 24 h during 3 days. In this case we
References and notes
1. Recent reviews: (a) Giessert, A.; Diver, S. T. Chem. Rev.
2004, 194, 1317; (b) Mori, M. Ene–yne Metathesis. In
Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH:
Weinheim, 2003; Vol. 2, p 176; (c) Poulsen, C. S.; Madsen,
R. Synthesis 2003, 1; (d) Trnka, T. M.; Grubbs, R. H. Acc.
Chem. Res. 2001, 34, 18; (e) Furstner, A. Angew. Chem.,
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Int. Ed. 2000, 39, 3012; (f) Maier, M. E. Angew. Chem.,
Int. Ed. 2000, 39, 2073; (g) Grubbs, R. H.; Chang, S.
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2. See, for recent examples: (a) Barrett, A. G. M.; Hennessy,
A. J.; Vezouet, R. L.; Procopiou, P. A.; Seale, P. W.;
Stefaniak, S.; Upton, R. J.; White, A. J. P.; Williams, D. J.
J. Org. Chem. 2004, 69, 1028; (b) Mori, M.; Tomita, T.;
Kita, Y.; Kitamura, T. Tetrahedron Lett. 2004, 45, 4397;
(c) Brenneman, J. B.; Martin, S. F. Org. Lett. 2004, 6,
1329.

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A. Gonza´lez-Go´mez et al. / Tetrahedron Letters 46 (2005) 7267–7270
7270
´
3. Recent tandem dienyne metathesis examples: (a) Garcıa-
(br s, 1H), 6.30 (s, 1H), 6.59 (d, 2H, J = 8.2 Hz), 6.97 (d,
1H, J = 7.7 Hz), 7.01–7.13 (m, 3H), 7.24 (d, 1H,
J = 7.7 Hz), 7.62 (d, 2H, J = 8.2 Hz). 13C NMR (C6D6,
60 °C) d (ppm): 20.3, 21.0, 42.9, 46.8, 53.1, 106.1, 109.5,
115.4, 118.8, 119.9, 120.2, 121.6, 127.3, 128.4, 129.5, 129.9,
131.5, 134.5, 137.7, 139.1, 143.1. IR (KBr) m 1600, 1340,
1160 cmÀ1. MS (ESI) m/z 391 (M+H). Anal. Calcd for
C23H22N2O2S: C, 70.74; H, 5.68; N, 7.17. Found: C, 70.99;
H, 5.89; N, 7.08.
´
Fandino, R.; Codesido, E. M.; Sobarzo-Sanchez, E.;
˜
Castedo, L.; Granja, J. R. Org. Lett. 2004, 6, 193; (b)
Honda, T.; Namiki, H.; Kaneda, K.; Mizutani, H. Org.
Lett. 2004, 6, 87; (c) Fukumoto, H.; Esumi, T.; Ishihara,
J.; Hatakeyama, S. Tetrahedron Lett. 2003, 44, 8047; (d)
Boyer, F.-D.; Hanna, I.; Ricard, L. Org. Lett. 2001, 3,
3095; (e) Choi, T.-L.; Grubbs, R. H. Chem. Commun.
2001, 2648; (f) Furstner, A.; Liebl, M.; Hill, A. F.; Wilton-
Ely, J. D. E. T. Chem. Commun. 1999, 601; (g) Zuercher,
W. J.; Scholl, M.; Grubbs, R. H. J. Org. Chem. 1998, 63,
4291; (h) Kim, S.-H.; Zuercher, W. J.; Bowden, N. B.;
Grubbs, R. H. J. Org. Chem. 1996, 61, 1073.
8. For other examples of the beneficial effect of ethylene see:
(a) Mori, M.; Kuzuba, Y.; Kitamura, T.; Sato, Y. Org.
Lett. 2002, 4, 3855; (b) Saito, N.; Sato, Y.; Mori, M. Org.
Lett. 2002, 4, 803.
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4. Rosillo, M.; Domınguez, G.; Casarrubios, L.; Amador,
9. Alcaide, B.; Almendros, P. Chem. Eur. J. 2003, 9,
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U.; Perez-Castells, J. J. Org. Chem. 2004, 69, 2084.
5. See: (a) Sanford, M. S.; Love, J. A.; Grubbs, R. H. J. Am.
Chem. Soc. 2001, 123, 6543; (b) Sanford, M. S.; Ulman,
M.; Grubbs, R. H. J. Am. Chem. Soc. 2001, 123, 749; (c)
Aagaard, O. M.; Meier, R. J.; Buda, F. J. Am. Chem. Soc.
1998, 120, 7174.
6. An aliquot was taken from the reaction every 12 h, and
after workup the crude was analyzed by 1H NMR showing
progressive conversion of 6a into 10a.
7. Experimental procedure for the synthesis of 10a is as
follows: To a 0.01 M solution of 6a (0.200 g, 0.512 mmol)
in anhydrous toluene, 0.022 g (0.026 mmol) of Grubbs
catalysts B was added and the resulting mixture was
stirred at room temperature under a ethylene atmosphere
for 3 h. The reaction mixture was filtered off through a
Celite pad and washed with toluene. The solvent was
removed under reduced pressure and purified by column
chromatography (hexane–EtOAc, 9:1) giving pure 10a
(0.190 g, 95%) as yellow oil. 1H NMR (C6D6, 60 °C) d
(ppm): 1.76 (s, 3H), 2.17–2.21 (m, 2H), 3.88–4.05 (m, 4H),
5.11 (d, 1H, J = 12.1 Hz), 5.48 (d, 1H, J = 17.0 Hz), 5.68
10. Synthesis of 15: to a solution of 7 (0.150 g, 0.543 mmol) in
anhydrous toluene (30 mL), 7 mg (0.011 mmol) of Grubbs
C complex were added every 24 h during 3 days while
stirring at 80 °C. The reaction mixture was filtered off
through a Celite pad and washed with dry toluene
(20 mL). The solvent was removed under reduced pressure
and the residue purified by column chromatography
(hexane–EtOAc 49:1) giving 15 (0.101 g, 67%) as a yellow
1
oil. H NMR (CDCl3) d (ppm): 3.16 (t, 2H, J = 6.8 Hz),
4.22 (t, 2H, J = 6.8 Hz), 4.82 (d, 2H, J = 5.5 Hz), 5.61–
5.69 (m, 1H), 6.14 (d, 1H, J = 2.7 Hz), 6.65 (d, 1H, J =
11.0 Hz), 6.70 (d, 1H, J = 2.7 Hz), 7.11 (td, 1H,
J1 = 7.7 Hz, J2 = 1.1 Hz), 7.18 (td, 1H, J1 = 8.2 Hz, J2 =
1.1 Hz), 7.34 (d, 1H, J = 8.2 Hz), 7.51 (d, 1H, J = 7.7 Hz).
13C NMR (CDCl3) d (ppm): 21.4, 44.0, 45.2, 103.0, 107.4,
109.3, 116.1, 116.5, 117.8, 119.6, 121.0, 121.7, 127.5, 127.6,
128.3, 130.0, 137.2. IR (neat) m 1620, 1600 cmÀ1. MS
(APCI), m/z: 247 [M+H]+. Anal. Calcd for C17H14N2: C,
82.90; H, 5.73; N, 11.37. Found: C, 82,72; H, 5.67; N,
11.48.