A concise route to indoloazocines via a sequential Ugi-gold-catalyzed intramolecular hydroarylation

Article abstract of DOI:10.1039/c2cc32586a

A diversity oriented approach for the synthesis of indoloazocines is reported employing an Ugi reaction followed by a gold-catalyzed intramolecular hydroarylation.

Full text of DOI:10.1039/c2cc32586a

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2012, 48, 6550–6552
www.rsc.org/chemcomm
COMMUNICATION
A concise route to indoloazocines via a sequential Ugi–gold-catalyzed
intramolecular hydroarylationw
Sachin G. Modha,a Dipak D. Vachhani,a Jeroen Jacobs,b Luc Van Meerveltb and
Erik V. Van der Eycken*a
Received 11th April 2012, Accepted 8th May 2012
DOI: 10.1039/c2cc32586a
A diversity oriented approach for the synthesis of indoloazocines is
reported employing an Ugi reaction followed by a gold-catalyzed
intramolecular hydroarylation.
access to complex molecules in few steps as compared to traditional
multistep processes. As a result of our recent endeavours regarding
the chemistry of the indole core,6,9 multicomponent reactions10 and
transition-metal-catalysis,11 a concise diversity oriented approach
towards indoloazocines was developed. Compound 5a was synthe-
sized by Ugi reaction8 of tryptamine with p-methoxy benzaldehyde,
tBu-isonitrile and 2-butynoic acid in methanol at rt. This readily
formed compound 5a was used for investigating the intramolecular
hydroarylation to furnish indoloazocine 6a. When 5 mol% of
Hg(OTf)2 was used as catalyst6a in CDCl3, only 30% conversion
was observed after 20 h at rt. The conversion was improved to
50% when 5 mol% of AgOTf was employed (Table 1, entries 1
and 2). No amelioration was observed with AuCl, AuCl3,
Au(PPh3)Cl, FeCl3, p-tolylsulfonic acid and Yb(OTf)3
(Table 1, entries 3–8).7p
Indoloazocines are important members of the indole containing
alkaloid family and challenging synthetic targets. Some members
are deoxyisoaustamide,1 okaramine N2 and balasubramide3
(Fig. 1). Despite its importance, this framework is scarcely
investigated, and reports generally deal with multistep processes,
which limits the scope and diversity.4 Addressing this issue,
Echavarren and co-workers have recently reported a gold-catalyzed
intramolecular hydroarylation procedure giving access to a short
route to the indoloazocine framework.5a,b We have recently
developed an intramolecular carbocyclization for the construc-
tion of azocino[b]-indoles and an intramolecular reductive Heck
reaction for the generation of azocino[cd]indoles.6 Although
such transition-metal-catalyzed transformations7 are rising to
prominence, the synthesis of the starting materials via an
elaborate multi-step sequence is mostly required, thereby
hampering the introduction of much diversity.
Table 1 Optimization of the intramolecular hydroarylationa
Through the years, multicomponent reactions (MCRs)8 have
received increasing attention due to their simplicity, efficiency, atom
economy, shortened reaction times, and diversity oriented synthesis.
The combination of MCRs with transition-metal-catalysis gives
Temp/ Conversion (%)
(Yield (%))b
Entry Catalyst (mol%) Solvent Time/h 1C
1
2
3
4
5
6
7
Hg(OTf)2 (5)
AgOTf (5)
AuCl (5)
AuCl3 (5)
Au(PPh3)Cl (5)
FeCl3 (5)
p-tolylsulfonic
acid (5)
Yb(OTf)3 (5)
Au(PPh3)OTf (5) CDCl3
Au(PPh3)OTf (5) CDCl3
Au(PPh3)OTf (5) CDCl3
Au(PPh3)OTf (5) DCM-d2
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
20
20
20
20
20
20
20
rt
rt
rt
rt
rt
rt
rt
30 (20)
50 (35)
Traces
0
0
0
0
8
9
CDCl3
20
8
4
4
8
rt
rt
50
80
rt
rt
rt
rt
rt
0
Fig. 1 Alkaloids containing the indoloazocine core.
100 (85)
40
25
10
11
12
13
14
15
16
a Laboratory for Organic & Microwave-Assisted Chemistry
(LOMAC), Department of Chemistry, KU Leuven,
Celestijnenlaan 200F, B-3001, Leuven, Belgium.
100 (82)
0
Traces
Au(PPh3)OTf (5) ACN-d3 20
Au(PPh3)OTf (5) THF-d8 20
Au(PPh3)OTf (5) MeOH 20
E-mail: erik.vandereycken@chem.kuleuven.be
b Biomolecular Architecture, Department of Chemistry, KU Leuven,
Celestijnenlaan 200F, B-3001, Leuven, Belgium
w Electronic supplementary information (ESI) available: Experimental
procedures, X-ray crystal and spectral data. CCDC 873949. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c2cc32586a
c
—
80
Au(PPh3)OTf (3) CDCl3
20
a
b
All reactions were run on a 0.1 mmol scale of 5a. Conversion based
on 1H NMR analysis; yields (in parentheses) are isolated yields.
c
Addition of methanol on triple bond was observed.
c
6550 Chem. Commun., 2012, 48, 6550–6552
This journal is The Royal Society of Chemistry 2012

View Article Online
Table 2 Scope of the hydroarylation process
To reduce the reaction time the cyclization was performed
at elevated temperature, however, the conversion dropped
significantly (Table 1, entries 10 and 11). While changing the
solvent to dichloromethane resulted in similar results, no
conversion was observed in acetonitrile and only traces of
product were formed in tetrahydrofuran (Table 1, entries
12–14). The reaction was also tried in methanol, aiming at
the possibility of developing a one-pot two-step process.
However, addition of methanol to the triple bond12 occurred
(Table 1, entry 15). Reducing the catalyst loading to 3 mol%
resulted in 80% conversion in 20 h (Table 1, entry 16).
The optimized conditions (Table 1, entry 9) were applied on
the diversely substituted Ugi adducts 5a–q. In most of the
cases the indoloazocines could be obtained in good to excellent
yields (Table 2). In the case of compounds 5n and 5p, no
cyclized product formed possibly due to steric hindrance of the
bulky phenyl and t-butyl substituents on the alkyne fragment
(Table 2, entries 14 and 16). Surprisingly the terminal alkyne
5q gave the 7-exo-dig product 6q (Table 2, entry 17), possibly
due to a metal carbene intermediate stage as described by
Echavarren and co-workers.5
Entry
Ugi adduct 5 (yield)
Indoloazocine 6 (yield)
1
2
3
4
5
6
5a, R = 4-MeOC6H4, (82%) 6a, R = 4-MeOC6H4, (85%)
5b, R = Cy, (95%) 6b, R = Cy, (84%)
5c, R = t-Bu, (89%) 6c, R = t-Bu, (90%)
5d, R = 2,6-diClC6H4, (76%) 6d, R = 2,6-diClC6H4, (91%)
5e, R = Phenethyl, (75%)
5f, R = furan-2-yl, (43%)
6e, R = Phenethyl, (85%)
6f, R = furan-2-yl, (72%)
7
8
5g, R = Cy, (84%) 6g, R = Cy, (88%)
5h, R = 2,6-diClC6H4, (84%) 6h, R = 2,6-diClC6H4, (89%)
Having investigated the scope and limitations of the optimized
protocol on tryptamine derivatives, we investigated L-tryptophan
methylester as the starting material. After Ugi reaction a mixture
of two diastereoisomers was obtained, which was separated by
column chromatography. Both diastereoisomers could be
cyclized resulting in the formation of pure diastereoisomeric
indoloazocines in good yields (Table 3). Structures of these
diastereoisomers were unambiguously assigned as being 6r
(S,S) and 6s (S,R) by X-ray crystallography (Scheme 1).
A plausible mechanism5,13 is depicted in Scheme 2. Nucleo-
philic attack of the 3-position of the indole core on the
activated alkyne could give spiro intermediate B.14 This on
1,2-shift produces intermediate C which on deprotonation and
protodeauration forms indoloazocine 6.
9
10
5i, R = Cy, (88%) 6i, R = Cy, (89%)
5j, R = 2,6-diClC6H4, (91%) 6j, R = 2,6-diClC6H4, (80%)
11
12
5k, R = n-pentyl, (34%)
5l, R = Cy, (48%)
6k, R = n-pentyl, (85%)
6l, R = Cy, (65%)
In summary, we have developed a concise diversity oriented
approach to indoloazocines. The merits of this method are mild
reaction conditions, good to excellent yields, the introduction of
four points of diversity due to the Ugi 4CR, and selectivity for
13
14
5m, R = Et, (82%)
5n, R = Ph, (75%)
6m, R = Et, (85%)
6n, R = Ph, (0%)
Table 3 Expanding the scope of the hydroarylation process
Entry
Ugi adduct 5 (yield)
Indoloazocine 6 (yield)
1
15
16
5o, R = i-Pr (86%)
5p, R = t-Bu (84%)
6o, R = i-Pr (81%)
6p, R = t-Bu (0%)
5r, (14%)a
6r, (62%)
17
2
5q, (92%)
6q, (56%)
5s, (29%)a
6s, (49%)
A cationic gold complex,7i formed in situ by mixing 5 mol%
of Au(PPh3)Cl and AgOTf, turned out to be the best catalyst
giving 100% conversion in 8 h at rt (Table 1, entry 9).
a
Yield of pure isolated diastereoisomer. Combined yield for the Ugi
reaction is 92% with a 65 : 35 diastereomeric ratio.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 6550–6552 6551

View Article Online
L. N. Kulikova, A. V. Varlamov, M. Catto, C. Altomare and
A. Carotti, Eur. J. Org. Chem., 2004, 3128.
5 (a) C. Ferrer and A. M. Echavarren, Angew. Chem., Int. Ed., 2006,
45, 1105; (b) C. Ferrer, C. H. M. Amijs and A. M. Echavarren,
Chem.–Eur. J., 2007, 13, 1358; (c) A. M. Echavarren, Nat. Chem.,
2009, 1, 431.
6 (a) P. A. Donets, K. Van Hecke, L. Van Meervelt and E. V.
Van der Eycken, Org. Lett., 2009, 11, 3618; (b) V. A. Peshkov,
S. Van Hove, P. A. Donets, O. P. Pereshivko, K. Van Hecke, L. Van
Meervelt and E. V. Van der Eycken, Eur. J. Org. Chem., 2011, 1837.
7 For transition-metal-catalyzed carbocyclizations see (a) I. Ojima,
M. Tzamarioudaki, Z. Li and R. J. Donovan, Chem. Rev., 1996,
96, 635; for platinum-catalyzed intramolecular hydroarylation
leading to azepinoindoles and their pyrrole analogues, see
(b) M. Gruit, A. Pews-Davtyan and M. Beller, Org. Biomol. Chem.,
2011, 9, 1148; (c) M. Gruit, D. Michalik, A. Tillack and M. Beller,
Angew. Chem., Int. Ed., 2009, 48, 7212; for gold-catalyzed tandem
approaches leading to polycyclic indoles, see (d) C. C. J. Loh,
J. Badorrek, G. Raabe and D. Enders, Chem.–Eur. J., 2011,
17, 13409; (e) Y. Lu, X. Du, X. Jia and Y. Liu, Adv. Synth. Catal.,
2009, 351, 1517; (f) X. Xie, X. Du, Y. Chen and Y. Liu, J. Org.
Chem., 2011, 76, 9175; for a gold-catalyzed approach towards
tetracyclic indolines, see (g) G. Cera, P. Crispino, M. Monari and
M. Bandini, Chem. Commun., 2011, 47, 7803; (h) G. Cera,
M. Chiarucci, A. Mazzanti, M. Mancinelli and M. Bandini, Org.
Lett., 2012, 14, 1350; for gold-catalysis with an alkyne, see
Scheme 1 Crystal structure of compound 6s. Thermal ellipsoids are
drawn at the 50% probability level.w
´
(i) E. Jimenez-Nu´ nez and A. M. Echavarren, Chem. Commun.,
2007, 333; for gold-catalysis and platinum-catalysis in general, see
(j) A. Furstner and P. W. Davies, Angew. Chem., Int. Ed., 2007,
¨
46, 3410; (k) A. S. K. Hashmi and M. Rudolph, Chem. Soc. Rev.,
2008, 37, 1766; (l) M. Rudolph and A. S. K. Hashmi, Chem.
Commun., 2011, 47, 6536; (m) M. Rudolph and A. S. K. Hashmi,
Chem. Soc. Rev., 2012, 41, 2448; (n) C. Ferrer, A. Escribano-
Cuesta and A. M. Echavarren, Tetrahedron, 2009, 65, 9015;
(o) A. Furstner, Chem. Soc. Rev., 2009, 38, 3208; (p) A. S. K.
¨
Hashmi, L. Schwarz, P. Rubenbauer and M. C. Blamco, Adv.
Synth. Catal., 2006, 348, 705.
8 For multicomponent reactions based on isocyanide, see
(a) A. Domling and I. Ugi, Angew. Chem., Int. Ed., 2000,
¨
39, 3168; (b) A. Domling, Chem. Rev., 2006, 106, 17; for assym-
¨
Scheme 2 Plausible mechanism for the intramolecular hydroarylation.
metric multicomponent reactions, see (c) D. J. Ramo
Angew. Chem., Int. Ed., 2005, 44, 1602; (d) S. S. van Berkel,
B. G. M. Bogels, M. A. Wijdeven, B. Westermann and F. P. J. T.
Rutjes, Eur. J. Org. Chem., 2012, DOI: 10.1002/ejoc.201200030;
for multicomponent reactions in general, see (e) B. Ganem,
´
n and M. Yus,
the 8-endo-dig cyclization using a cationic gold complex. This
is a very facile method in terms of starting material avail-
ability, scope and diversity. Further expansion of this method
for the synthesis of alkaloid like structures is under current
investigation.
¨
Acc. Chem. Res., 2009, 42, 463; (f) L. El Kaım and L. Grimaud,
¨
Mol. Diversity, 2010, 14, 855; (g) E. Ruijter, R. Scheffelaar and
R. V. A. Orru, Angew. Chem., Int. Ed., 2011, 50, 6234;
Support was provided by the research fund of the KU
Leuven and the FWO (Fund for Scientific Research – Flanders
(Belgium)). DDV is thankful to EMECW, lot 13 (Erasmus
Mundus External Cooperation Window, Lot-13) for providing
a doctoral scholarship. The authors thank Ir. B. Demarsin for
HRMS measurements.
(h) A. Domling, W. Wang and K. Wang, Chem. Rev., 2012,
¨
DOI: 10.1021/cr100233r; for multicomponent processes with indole,
see (i) M. Shiri, Chem. Rev., 2012, DOI: 10.1021/cr2003954.
9 P. A. Donets and E. V. Van der Eycken, Synthesis, 2011, 2147.
10 V. P. Mehta, S. G. Modha, E. Ruijter, K. Van Hecke, L. Van
Meervelt, C. Pannecouque, J. Balzarini, R. V. A. Orru and
E. V. Van der Eycken, J. Org. Chem., 2011, 76, 2828.
11 (a) S. G. Modha, J. C. Trivedi, V. P. Mehta, D. S. Ermolat’ev and
E. V. Van der Eycken, J. Org. Chem., 2011, 76, 846;
(b) S. G. Modha, V. P. Mehta, D. Ermolat’ev, J. Balzarini,
K. Van Hecke, L. Van Meervelt and E. V. Van der Eycken, Mol.
Diversity, 2010, 14, 767; (c) V. P. Mehta and E. V. Van der Eycken,
Chem. Soc. Rev., 2011, 40, 4925; (d) V. A. Peshkov, O. P.
Pereshivko and E. V. Van der Eycken, Chem. Soc. Rev., 2012,
41, 3790; (e) C. O. Kappe and E. Van der Eycken, Chem. Soc.
Rev., 2010, 39, 1280.
12 (a) J. H. Teles, S. Brode and M. Chabanas, Angew. Chem., Int. Ed.,
1998, 37, 1415; (b) Y. Fukuda and K. Utimoto, J. Org. Chem.,
1991, 56, 3729; (c) M. Schuler, F. Silva, C. Bobbio, A. Tessier and
V. Gouverneur, Angew. Chem., Int. Ed., 2008, 47, 7927.
13 For a review on mechanistic aspects of gold-catalyzed reac-
tions, see A. S. K. Hashmi, Angew. Chem., Int. Ed., 2010, 49,
5232.
14 For a detailed study of spirointermediates in gold-catalysis, see
(a) A. S. K. Hashmi, W. Yang and F. Rominger, Angew. Chem.,
Int. Ed., 2011, 50, 5762; (b) A. S. K. Hashmi, W. Yang and
F. Rominger, Chem.–Eur. J., 2012, 18, 6576.
Notes and references
1 (a) P. S. Steyn, Tetrahedron Lett., 1971, 12, 3331; (b) P. S. Steyn,
Tetrahedron, 1973, 29, 107; (c) P. G. Sames, Fortschr. Chem. Org.
Naturst., 1975, 32, 51; (d) P. S. Baran and E. J. Corey, J. Am.
Chem. Soc., 2002, 124, 7904.
2 P. S. Baran, C. A. Guerrero and E. J. Corey, J. Am. Chem. Soc.,
2003, 125, 5628.
3 (a) M. B. Johansen, A. B. Leduc and M. A. Kerr, Synlett, 2007,
2593; (b) L. Yang, G. Deng, De. X. Wang, Z. T. Huang, J. P. Zhu
and M. X. Wang, Org. Lett., 2007, 9, 1387.
4 (a) R. Yoneda, T. Kimura, J. Kinomota, S. Harusawa and
T. Kurihara, J. Heterocycl. Chem., 1996, 33, 1909;
(b) J. Bonjoch, N. Casamitjana, J. Gracia, C. M. Ubeda and
J. Bosch, Tetrahedron Lett., 1990, 31, 2449; (c) S. Blechert,
R. Knier, H. Schroers and T. Wirth, Synthesis, 1995, 592;
(d) K. Diker, M. Doe de Maindreville and J. Levy, Tetrahedron
Lett., 1995, 36, 3511; (e) L. G. Voskressensky, T. N. Borisova,
c
6552 Chem. Commun., 2012, 48, 6550–6552
This journal is The Royal Society of Chemistry 2012