Synthesis of azocino[5,4-b]indoles via gold-catalyzed intramolecular alkyne hydroarylation

Article abstract of DOI:10.1002/adsc.201200305

An efficient procedure for the synthesis of the azocinoACHTUNGTRENUNG[5,4- b]indole framework is presented, relying on a cationic gold-catalyzed intramolecular alkyne hydroarylation of propargylic amides derived from various tryptamines and 3-substituted

Full text of DOI:10.1002/adsc.201200305

UPDATES
DOI: 10.1002/adsc.201200305
Synthesis of Azocino
N
Vsevolod A. Peshkov,a Olga P. Pereshivko,a and Erik V. Van der Eyckena,*
a
Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, University of Leuven
(KU Leuven), Celestijnenlaan 200F, B-3001 Leuven, Belgium
Fax : (+32)-16-32-79-90; e-mail: erik.vandereycken@chem.kuleuven.be
Received: April 12, 2012; Revised: June 9, 2012; Published online: September 28, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200305.
Abstract: An efficient procedure for the synthesis
of the azocino[5,4-b]indole framework is presented,
b]indole and azocinoACTHNGUTERNNUG
[4,5-b]indole cores.[12] The reac-
tion outcome was shown to be strongly dependent on
the nature of the employed gold catalyst. While the
strong cationic Au(I) complex (JohnPhosAu-
G
relying on a cationic gold-catalyzed intramolecular
alkyne hydroarylation of propargylic amides de-
rived from various tryptamines and 3-substituted 2-
propynoic acids. The triphenylphosphinegold(I)
chloride/silver(I) triflate catalytic system was found
to be superior to our previously described mercu-
ry(II) triflate catalyst, and hence the substrate
scope of the process was significantly expanded.
MeCN)SbF6 gave rise to azepino
ing an exocyclic double bond, AuCl3 generally provid-
ed the azocino[4,5-b]indoles 2 as the major product
along with azepino[4,5-b]indoles 3 bearing migrated
ACHTUNGERTN[NUNG 4,5-b]indoles 1 bear-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
endocyclic double bond (Scheme 1). Inspired by
Echavarrenꢀs procedure, we have recently established
a microwave-assisted Hg
ACHTUNGRTEN(NUNG OTf)2-catalyzed intramolec-
ular alkyne hydroarylation reaction for the synthesis
À
Keywords: C C coupling; cyclization; gold cataly-
sis; medium-ring compounds; nitrogen heterocycles
of variously substituted azocinoACHTUNTRGNEUNG[4,5-b]indoles of type
4 (Scheme 1).[13]
Since most of the inorganic and organic mercury
compounds are highly toxic, we were searching for an
alternative catalytic system to replace HgACTHNUGTRENUNG(OTf)2 in
Indole-annulated medium-sized rings are important our process. However, as earlier attempts to employ
heterocyclic motifs occurring in both natural and syn- other Lewis acid catalysts such as AuCl, AuCl3,
thetic products. Nitrogen-containing seven- and eight- AgOTf, AgO2CCF3, PdCl2 and PtCl2 met with fail-
membered rings are the most widespread[1] and have ure,[13] we switched our attention to strong cationic
been constructed employing various methods includ- Au(I) complexes.[14] Herein we wish to report our
ing intramolecular Friedel–Crafts alkylation,[2] intra- findings in this area and we will give a brief compari-
molecular radical cyclization,[3] ring-closing metathe- son with our previous results.[15]
sis,[3b,4] classical[5] and oxidative[6] Heck reaction, one-
pot/tandem multi-component
processes,[7]
proaches[8] and ring-expansion protocols.[9] We have cationic Au(I) species. Therefore we set up a number
recently described the assembly of azocino[4,5,6- of small-scale experiments with propargylic amide 5a
cd]indoles and azepino[4,5-b]indoles via an intramo- and various Au/Ag-catalytic systems in deuterated
A combination of monophosphine Au(I) chlorides
ap- with various Ag(I) salts is known to produce in situ
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
lecular reductive Heck reaction (formal hydroaryla- chloroform allowing direct recording of 1H NMR
tion of the triple bond).[10] The main disadvantage of spectra (Table 1). The application of 5 mol% of
this method is the difficult accessibility of halogenated AuPPh3Cl/AgOTf resulted in a 100% conversion of
indole precursors. Therefore direct hydroarylation of 5a within 4.5 h (Table 1, entry 1). It is worth noting
the triple bond might be viewed as an attractive alter- that this reaction was extremely clean as besides the
native that can provide fast access towards complex desired product 4a and phosphine ligand no by-prod-
1
indole-fused medium-sized rings starting from easily ucts were observed in the H NMR spectrum of the
available precursors.[11]
reaction mixture.[16] Application of 5 mol% of Au
ACHTUNGTRENNUNG(X-
This concept was for the first time successfully real- Phos)Cl/AgOTf resulted in a 91% conversion of 5a
ized by Echavarren and co-workers by applying gold for the same time (Table 1, entry 2). Also the use of
catalysis for the construction of the azepinoACHTUNGTRNEUNG[4,5- 5 mol% of AuPPh3Cl/AgSbF6 or AuPPh3Cl/AgNTf2
Adv. Synth. Catal. 2012, 354, 2841 – 2848
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Vsevolod A. Peshkov et al.
UPDATES
Scheme 1. Various approaches towards azocinoACTHNUGRTNENUG[4,5-b]indoles and azepinoACHTUNGTNER[NUGN 4,5-b]indoles involving an intramolecular hydroar-
ylation of the triple bond.
both led to decreased conversions of 80% and 66% ature (Table 1, entry 7), although with moderate heat-
respectively (Table 1, entries 3 and 4). AuPPh3Cl ing at 608C for 2 h a low conversion of 20% was ob-
alone or together with AgO2CCF3 resulted in a no tained (Table 1, entry 8). Surprisingly the addition of
conversion of starting propargylic amide 5a (Table 1, 20 mol% of triphenylphosphine ligand completely in-
entries 6 and 5). Similarly no conversion was observed hibited the above reaction (Table 1, entry 9). We have
when employing 10 mol% of AgOTf at room temper- already mentioned in the previous study that Brøn-
Table 1. Screening of various catalytic systems for the intramolecular alkyne hydroarylation leading to azocino
4a.[a]
ACHTUNGTREN[NUNG 4,5-b]indole
Entry
Catalyst
Conditions
Conversion [%][b]
1
2
3
4
5
6
7
8
9
10
5 mol% AuPPh3Cl/AgOTf
r.t., 4.5 h
r.t., 4.5 h
r.t., 4.5 h
r.t., 4.5 h
r.t., 4.5 h or 508C, 2 h
r.t., 4.5 h or 508C, 2 h
r.t., 2 h
608C, 2 h
608C, 7 h
100[c]
91[d]
80[d]
66[d]
0
5 mol% Au
N
5 mol% AuPPh3Cl/AgSbF6
5 mol% AuPPh3Cl/AgNTf2
5 mol% AuPPh3Cl/AgO2CCF3
5 mol% AuPPh3Cl
10 mol% AgOTf
10 mol% AgOTf
0
0
20[e]
0
10 mol% AgOTf/20 mol% PPh3
5 mol% TfOH
r.t. or 608C, 2 h
0
[a]
Reactions were carried out on a 0.1 mmol scale of 5a in CDCl3 (0.5 mL).
Determined by H NMR directly after the indicated reaction time with respect to starting propargylic amide 5a.
Completion of the reaction was first confirmed by TLC.
[b]
[c]
[d]
1
The relation between the reaction time and conversion is not completely accurate in these cases as reaction still goes
1
during H NMR measurements.
[e]
After 2 h the reaction stops presumably due to precipitation of the catalyst as a silver mirror.
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Adv. Synth. Catal. 2012, 354, 2841 – 2848

Synthesis of AzocinoACTHNUGRTNEUNG[5,4-b]indoles via Gold-Catalyzed Intramolecular Alkyne Hydroarylation
Table 2. Scope of the novel AuPPh3Cl/AgOTf-catalyzed intramolecular alkyne hydroarylation protocol leading to azocino-
[4,5-b]indoles 4.
ACHTUNGTRENNUNG
[c]
Entry[a]
1
5
Conditions
r.t., 6 h
Product 4
Yield[b]
99
Yield with HgACTHUNGTERNNU(G OTf)2
5a
4a
85 (MW) or 95 (conv)
2
3
4
5b
5c
5d
r.t., 7 h
r.t., 16 h
508C, 2 h
4b, R3 =Me
4c, R3 =i-Pr
4d, R3 =Ph
92
91
95
86
79
61
5
6
5e
5f
508C, 2 h
508C, 2 h
4e, R3 =Me
4f, R3 =Ph
82
88
75
58
7[d]
5g
5h
5i
508C, 20 h
4g
4h
4i
72
78
0
8[d]
508C, 8 h
508C, 38 h
26 (52)[e]
48
9[d,f]
10[d]
508C, 12 h
508C, 68 h
10 (21)[e]
27
11[d,g]
[h]
–
[h]
12[d]
13[d]
5j
5k
r,t„ 22 h
508C, 2 h
4j, R3 =Me
4k, R3 =Ph
93
81
–
–
[h]
[f]
[h]
14
5l
508C, 68 h
4l
70
–
[a]
Reactions were carried out on a 0.4-mmol scale, unless otherwise specified.
Isolated yields.
[b]
[c]
[d]
[e]
[f]
From ref.[13]
Carried out on a 0.3-mmol scale.
Yields based on recovered starting material are given in parenthesis.
10 mol% of catalysts were used.
15 mol% of catalysts were used (added in two portions: first 10 mol% followed by 5 mol% after 16 h).
No data.
[g]
[h]
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
ed to evaluate reaction with TfOH more precisely reactions catalyzed by 5 mol% of TfOH after 2 h at
since Au/Ag catalytic systems might produce in situ room temperature or 608C (Table 1, entry 10) con-
small quantities of strong protic acid which could be firming that our alkyne hydroarylation process is
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Vsevolod A. Peshkov et al.
UPDATES
most likely catalyzed by cationic Au(I) species. On i. These reactions were rather sluggish and unclean
the basis of this catalyst screening the AuPPh3Cl/ therefore the corresponding final azocino[4,5-b]in-
AgOTf combination was chosen for the further elabo- doles 4h, i required additional purification by recrys-
AHCTUNGTRENNUNG
ration.
tallization after the column chromatography (Table 2,
Next we investigated the scope and limitations of entries 8–11).
the process. In most cases the AuPPh3Cl/AgOTf cata-
lytic system was found to be superior to the previous- the Hg
ly described Hg(OTf)2-catalyst delivering target indo- acid derived propargylic amides 5m, n containing
In our previous study we have demonstrated that
AHCTUNGRTEN(NGUN OTf)2-catalyzed cyclization of 2-propynoic
ACHTUNGTRENNUNG
loazocines 4 in improved yields (Table 2, entries 1–7). a terminal triple bond in contrast to other substrates
A small drop of the yield was only observed for the proceeds in exo-fashion thus resulting in a formation
reaction with TIPS-O-protected propargylic amide 5g of azepinoACTHNUTRGNEU[GN 4,5-b]indoles 6m, n (Table 3, entries 1 and
(Table 2, entry 8). The best yield improvement was 6).[17] The novel AuPPh3Cl/AgOTf-catalyzed protocol
achieved in the reactions with propargylic amides 5d being applied to substrates 5m, n also operated
and 5f derived from 3-phenyl-2-propynoic acid through the exo-mode. However, in both cases in ad-
(Table 2, entries and 6). More importantly, in case of dition to azepino
the reaction with l-tryptophan derivative 5h where considerable amounts of other exo-cyclized product,
Hg(OTf)2 completely failed, the application of the spiro-fused indole derivative 7m/7n, was observed
ACHTUNGTRENN[UNG 4,5-b]indole 6m/6n the formation of
ACHTUNGTRENNUNG
novel AuPPh3Cl/AgOTf-catalyzed protocol allowed (Table 3, entries 2 and 7). Also in reaction with prop-
us to obtain the desired indoloazocine 4h in 26% argylic amide 5m a small amount of endo-cyclized
yield (Table 2, entry 8). This yield could be further in- azocino
creased by applying higher catalyst loading entry 2).
(10 mol%) and a prolonged reaction time (Table 2, From the operational point of view, the AuPPh3Cl/
ACHTUNGTRENN[UNG 4,5-b]indole 4m was detected (Table 3,
a
entry 9). Encouraged by this result we decided to test AgOTf-catalyzed protocol allowed to achieve full
one more l-tryptophan-derived substrate 5i (Table 2, conversion of starting propargylamides 5m, n in 24 h
entries 10 and 11). Similarly to the previous case the at room temperature (Table 3, entries 2 and 7). Carry-
yield of the desired indoloazocine 4i could be im- ing out the AuPPh3Cl/AgOTf-catalyzed cyclization of
proved through increasing the catalyst loading and 5m at 508C shortened the reaction time but did not
the reaction time.
significantly affect the reaction outcome (Table 3,
Next we decided to extend the applicability of our entry 3). Surprisingly the application of AgOTf
new protocol to the synthesis of indoloazocines bear- (10 mol%) as a sole catalyst at increased temperature
ing substituents on the indole core. To our great satis- of 608C not only resulted in unexpectedly[18] high con-
faction, propargylamides 5j, k derived form N-benzyl- versions of 5m, n but also changed the mode of cycli-
5-methoxytryptamine could be successfully cyclized zation to the endo/exo competition (Table 3, entries 4
employing the standard catalyst loading (5 mol%). and 8). As a result endo-cyclized azocinoACTHUNRTGNE[GNU 4,5-b]in-
The corresponding indoloazocines 4j, k were obtained doles 4m and 4n were isolated and characterized. Fur-
1
in good yields of 93% and 81%, respectively (Table 2, thermore, the precise analysis of the H NMR-spec-
entries 12 and 13). Remarkably, substrate 5l compris- trum of the reaction mixture (Table 3, entry 4) re-
ing the N-methylated indole was also found to be ap- vealed the formation of endo-cyclized spiro-fused
plicable. Carrying out the cyclization with an in- indole 8m.[16] The addition of 20 mol% of triphenyl-
creased catalyst loading (10 mol%) we were able to phosphine ligand returned the AgOTf-catalyzed reac-
synthesize the indoloazocine 4l in a good yield of tion into the exo-mode and again dramatically slowed
70% (Table 2, entry 14).
down the general cyclization rate (Table 3, entry 5).
On the basis of the substrate scope investigation
Formation of spiro cyclized indoles 7 and 8 might
some general conclusions can be drawn. Propargylic be considered as an indirect evidence for the mecha-
amides 5a–c, j derived from both (3-alkyl)-2-propyno- nism (Scheme 2) which was previously proposed by
ic acids and simple tryptamines (R2 =R5 =H) could Echavaren for the similar process. The triple bond ac-
be efficiently converted into the corresponding indo- tivated by the metal catalyst first reacts with the 3rd,
loazocines 4a–c, j employing a standard catalyst load- the most reactive, position of the indole core via exo-
ing of 5 mol% at room temperature. However, in the or endo-mode resulting in the formation of spiro-
case of the more complex tryptamine/tryptophan de- fused intermediates A or B, respectively. Subsequent
rivatives 5e–i, l or 3-phenyl-2-propynoic acid amides proton transfer in these intermediates could provide 7
5d, f, k a higher reaction temperature of 508C and in and 8 with concomitant demetalation. However, more
some cases an increased catalyst loading were needed commonly A/B further rearranges into C/D by a 1,2-
to achieve an acceptable conversion rate.
shift followed by formation of the ring expanded
Generally, most of the AuPPh3Cl/AgOTf-catalyzed product 6/4. The terminal character of the reacting
reactions were found to be clean and high yielding triple bond in the propargylic amides 5m, n seems to
with the exception of the l-tryptophan derivatives 5h, be a crucial factor facilitating the exo-mode of pro-
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Synthesis of AzocinoACTHNUGRTNEUNG[5,4-b]indoles via Gold-Catalyzed Intramolecular Alkyne Hydroarylation
Table 3. Cyclization of propargylic amides 5m, n containing the terminal triple bond.
Entry[a]
5
Catalyst; Conditions
Yield[b]
6
7
4
8
1[c]
2
5m, R1 =Me 5 mol% Hg
N
21
nd[d]
nd[d]
nd[d]
nd[d]
5 mol% AuPPh3Cl/AgOTf; r.t., 24 h, CHCl3 (CDCl3) 24 (25)[e] 15 (30)[e]
–
–
[f] (4)[e]
[f] (5)[e]
[f]
3[g]
4
5 mol% AuPPh3Cl/AgOTf; 508C, 7 h, CDCl3
10 mol% AgOTf; 608C, 6 h, CHCl3 (CDCl3)
10 mol% AgOTf/20 mol% PPh3; 608C, 6 h, CDCl3
–
(25)[e]
–
[f] (29)[e]
7 (23)[e]
[f] (9)[e]
nd[d]
nd[d]
9 (10)[e]
29 (31)[e]
nd[d]
–
(2)[e]
[f]
5[g,h]
6[c]
7
nd[d]
–
nd[d]
nd[d]
nd[d]
5n, R1 =Bn
5 mol% Hg
25
nd[d]
5 mol% AuPPh3Cl/AgOTf; r.t., 24 h, CHCl3 (CDCl3) 25 (26)[e] 25 (30)[e] nd[d]
8[i]
10 mol% AgOTf; 608C, 6 h, CHCl3 (CDCl3)
–
(4)[e]
–
[f] (5)[e]
14 (21)[e] nd[d]
[f]
[a]
Reactions were carried out on a 0.4-mmol scale, unless otherwise specified.
Isolated yields.
[b]
[c]
[d]
[e]
From ref.[13] (carried out on a 0.6-mmol scale).
nd=not detected.
1
Yields in parenthesis are determined by H NMR from the corresponding 0.1-mmol scale reaction in CDCl3 using 3,4,5-
trimethoxybenzaldehyde as internal standard.
Not determined.
Carried out on a 0.1-mmol scale.
No full conversion of 5m was achieved; 70% remained unreacted as was determined by H NMR.
No full conversion of 5n was achieved; 19% remained unreacted as was determined by H NMR.
[f]
[g]
[h]
[i]
1
1
cess. This could be ascribed to the fact that the metal
(OTf)+, Au(PPh3)+ and Ag(PPh3)+ apparently does
ACHTUNGTRNEUNGN ACHTNUGTRENNUNG ACTHNUGTRENNGUN
activator [M+] tends to coordinate closer to the termi- not differentiate between triple bond carbons. Conju-
nal carbon of the triple bond. The endo-mode for sub- gation of the triple bond with an electron-withdraw-
strates 5m, n could be partially realized only with ing amide group on the other hand seems to be less
AgOTf catalyst since Ag+ in contrast to bulkier Hg- strong factor as it does not promote attack of indole
Scheme 2. Mechanistic consideration of the process.
Adv. Synth. Catal. 2012, 354, 2841 – 2848
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Vsevolod A. Peshkov et al.
UPDATES
Scheme 3. Regioselective AuPPh3Cl/AgOTf-catalyzed intramolecular hydroalkoxylation of propargylic amide 5r.
to azocinoACTHNUTRGNEUG[N 5,4-b]indoles. A significant substrate scope
expansion was achieved by the application of some
previously unreactive substrates and substrates bear-
ing additional substituents on the indole core. A close
look at the reactions with terminal propargylic amides
resulted in the isolation and characterization of novel
cyclized products interesting for the mechanistic un-
derstanding of the process. The intramolecular hydro-
alkoxylation reaction leading to oxazepines is current-
ly under investigation in our laboratory and results
will be reported in due course.
Figure 1. Unsuitable substrates for the AuPPh3Cl/AgOTf-
catalyzed process.
Experimental Section
Full experimental details and spectroscopic data for all new
in endo-fashion in case of HgACTHNUTRGNEU(NG OTf)2-, AuPPh3Cl/
AgOTf- and AgOTf/PPh3-catalyzed cyclizations of
5m, n.
1
compounds along with the copies of H and 13C NMR spec-
tra are available as Supporting Information.
Unfortunately, we were not able to overcome all
limitations of the HgACTHNUTRGNE(NUG OTf)2-catalyzed procedure.
General Procedure for the AuPPh3Cl/AgOTf-
Catalyzed Intramolecular Alkyne Hydroarylation
(Table 2)
Thus, propargylic amide 5o derived from N-methyl-
tryptamine and 3-tert-butyl-2-propynoic acid, re-
mained unreacted under the novel AuPPh3Cl/AgOTf-
catalyzed conditions as well, presumably due to the
bulkiness of the t-Bu group. Secondary propargylic
amide 5p and propargylic amides 5q, r with an N-to-
sylated or N-acylated indole were also confirmed to
be unsuitable substrates for our hydroarylation pro-
cess (Figure 1). However, one of the previously un-
reactive substrates – 5s containing an unprotected hy-
droxy group – was found to possess other interesting
reactivity (Scheme 3). Being subjected to the
AuPPh3Cl/AgOTf-catalyzed procedure propargylic
Propargylic amide 5 (0.4 mmol) was dissolved in dry CHCl3
(2 mL). Subsequently AgOTf (5 mg, 0.02 mmol) and
AuPPh3Cl (10 mg, 0.02 mmol) were added. The reaction
mixture was allowed to stir at room temperature or 508C
for the indicated period of time in a sealed screw-cap vial
under air atmosphere. The resulting reaction mixture was
subjected to column chromatography to give the desired
azocinoACHTUNTRGNEU[GN 4,5-b]indole 4.
Acknowledgements
amide 5s did not provide the expected azocinoACTHNUGTRNEUNG[4,5-
b]indole 4s.[19] Instead an oxazepine 9 (major product)
was formed along with the corresponding six-mem-
bered morpholine 10 (minor product). Of course, this
result was not completely surprising considering the
Support was provided by the Fund for Scientific Research
(FWO), Flanders and by the Research Fund of the University
of Leuven (KU Leuven). V.A.P. is grateful to the EMECW
(Triple I) for providing a doctoral scholarship. The authors
thank Ir. B. Demarsin for HR-MS measurements. The au-
thors are also thoroughly grateful to all referees for their val-
uable advices.
known reactivity of oxygen nucleophiles in Au-cata-
[20]
ꢀ
lyzed additions to C C triple bonds. Nevertheless
this novel process might be anticipated as a convenient
and selective entry to the oxazepine core.
In summary, we have identified the AuPPh3Cl/
AgOTf catalytic system as an efficient replacement
References
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ACHTUNGTRENNUNG(OTf)2 catalyst in our previously developed
[1] For a short overview, see: P. A. Donets, Dissertation,
University of Leuven (KU Leuven, Belgium), 2011.
intramolecular alkyne hydroarylation reaction leading
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Synthesis of AzocinoACTHNUGRTNEUNG[5,4-b]indoles via Gold-Catalyzed Intramolecular Alkyne Hydroarylation
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ACHTUNGTRENNUNG
ACHTUNGTREN[NUNG 4,3-b]indole
AHCTUNGTRENNUNG
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ACHTUNGTRENNUNG
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[18] Before AgOTf catalyst showed poor results in the cycli-
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lamide 5a, see Table 1 (entries 7 and 8).
[19] AzocinoACTHNUGRTNEUNG[4,5-b]indole 4s could alternatively be prepared
by deprotection of 4g (see ref.[13]).
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[15] Simultaneously we have developed a diversity oriented
approach towards azocinoACTHNURGTNE[UNG 4,5-b]indoles employing se-
quential Ugi reaction followed by gold-catalyzed intra-
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[16] See Supporting Information for details.
[17] Initially in ref.[13] compounds 6m, n were assigned incor-
rectly, see additions and corrections: P. A. Donets, K.
Van Hecke, L. Van Meervelt, E. V. Van der Eycken,
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2848
asc.wiley-vch.de
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 2841 – 2848