Palladium(II)/N-Heterocyclic Carbene-Catalyzed Regioselective Heteroannulation of Tertiary Propargyl Alcohols and o-Haloanilines to form 2-Alkenylindoles

Article abstract of DOI:10.1002/adsc.201601349

Monometallic and bimetallic palladium(II)/N-heterocyclic carbene complexes appended with naphthalimide or bisnaphthalimide moieties were designed, synthesized, and characterized. Employment of these catalysts brings about the step-economic and regioselective heteroannulation of tertiary propargyl alcohols with o-haloanilines resulting in biologically and pharmaceutically relevant 2-alkenylindoles. Basis for the regioselective heteroannulation is unraveled by coordination of the propargylic hydroxy moiety to palladium during insertion. Embracing this methodology, a single regioisomer of unsymmetrical 2,3-disubstituted indoles could be achieved through late-stage modification. The role of the naphthalimide or bisnaphthalimide appended to the NHC on the catalytic efficiency has been studied. (Figure presented.).

Full text of DOI:10.1002/adsc.201601349

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DOI: 10.1002/adsc.201601349
Palladium(II)/N-Heterocyclic Carbene-Catalyzed Regioselective
Heteroannulation of Tertiary Propargyl Alcohols and
o-Haloanilines to form 2-Alkenylindoles
Pradeep Kumar Reddy Panyama and Thirumanavelan Gandhia,*
a
Department of Chemistry, School of Advanced Sciences, VIT University, Vellore – 632014, India
E-mail: velan.g@vit.ac.in
Received: December 7, 2016; Revised: December 15, 2016; Published online: && &&, 0000
Dedicated to Prof. Kenneth D. Karlin on the occasion of his 68th birthday.
Supporting information for this article can be found under: http://dx.doi.org/10.1002/adsc.201601349.
Abstract: Monometallic and bimetallic palladi-
ACHTUNGTRENNUNGum(II)/N-heterocyclic carbene complexes appended
sition.[6e] Traditionally, 2-alkenylindoles were synthe-
sized by the Wittig reaction[9] and hetero-Cope rear-
rangement.[10] In 2005, Gaunt[11] and co-workers dem-
onstrated a practical method for the synthesis of 2-al-
kenylindoles by tuning the solvent with free (NH) in-
doles mediated by palladium catalyst. Further,
palladium catalysts[5,6,12] proved their efficacy in con-
structing 2-alkenylindoles via Heck[13] and Stille cou-
pling,[14] and oxidative annulation reactions.[15] Despite
all these efforts, most of the reported methodologies
suffer from one or another drawbacks involving air-
and moisture-sensitive catalysts, high-catalyst loading,
activated olefins, multi-step processes, appropriate di-
recting groups, a stoichiometric amount of oxidants
and undesired by-products. Inspired by the Larock
heteroannulation,[16] we envisioned an alternative
pathway through which 2-alkenylindoles can be con-
structed in the absence of a vinylic coupling partner.
with naphthalimide or bisnaphthalimide moieties
were designed, synthesized, and characterized. Em-
ployment of these catalysts brings about the step-
economic and regioselective heteroannulation of
tertiary propargyl alcohols with o-haloanilines re-
sulting in biologically and pharmaceutically relevant
2-alkenylindoles. Basis for the regioselective hetero-
annulation is unraveled by coordination of the
propargylic hydroxy moiety to palladium during in-
sertion. Embracing this methodology, a single regio-
isomer of unsymmetrical 2,3-disubstituted indoles
could be achieved through late-stage modification.
The role of the naphthalimide or bisnaphthalimide
appended to the NHC on the catalytic efficiency
has been studied.
Keywords: alkenylindoles; N-heterocylic carbenes;
palladium; propargyl alcohols; regioselective annu-
lation
Indoles are fundamental structural motifs prevalent in
biologically active natural products, pharmaceuticals,
agrochemicals and functional materials.[1] In particu-
lar, 2-alkenylindoles exhibit very important pharma-
cological properties such as antimalarial,[2] anti-
ACHTUNGTRENNUNG
lipemic[3] and insecticidal activity[4] (Figure 1). A great
deal of chemistry has been accomplished on 3-
alkenylindoles, owing to the electron-rich nature of
the C-3 position whereas reports on the counterpart
2-alkenyl
indoles are limited.[5] Most commonly, access
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
to the C-2 position was achieved by installing a direct-
ing group with the intervention of a transition metal
Figure 1. Biologically relevant molecules with a 2-alkenylin-
catalyst (Pd,[6] Rh[7] and Ru[8]) or blocking the C-3 po- dole unit.
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The utility of metal-NHCs in catalysis is well with naphthalimide or bisnaphthalimide have been
known owing to their interesting electronic properties designed and synthesized. Azolium salts of naphthal-
and high thermal stability (resultant from strong coor-
ACHTUNGTRENiNUNG mides 1L–5L and bisnaphthalimide 6L, 7L were pre-
dination ability – better s-donating).[17] In addition, pared by treating the corresponding imidazoles with
installation of wide range of substitutents at the nitro- various alkyl/benzyl halides.[22] Palladation[18a] of 1L–
gen atoms of NHCs manifests asymmetric, steric, che- 7L with PdCl2 resulted in the formation of complexes
lating and p–p stacking features.[18] Reports on metal- 1C–7C, respectively, as orange-yellow solids ranging
NHC catalysts in Larock heteroannulation are from 55–80% yield. All the isolated Pd-NHC com-
scarce.[19] Our group has previously reported the plexes 1C–7C were characterized by multinuclear
Ru(II)-catalyzed regioselective deoxygenation–oxida- NMR and ESI-MS. Suitable crystals for X-ray diffrac-
tive annulation of propargyl alcohols with phthalazi- tion study were obtained by the slow diffusion of di-
nones and pyridazinones.[20] Propargyl alcohols, ethyl ether into dichloromethane solutions of 1C and
known for their contributions in the synthesis of het- 3C at ambient temperature. The molecular structures
erocyclic compounds,[21] leave vast scope for the gen- of 1C and 3C are shown in the Supporting Informa-
eration of new value-added entities involving organo- tion. The Pd–Ccarbene distance for 1C and 3C are
metallics. Herein, we disclose a straightforward, con- 1.960(5) and 1.959(2) ꢁ, respectively.[23]
venient, and one-pot synthesis of 2-alkenylindoles cat-
With the series of Pd-NHC complexes 1C–7C in
alyzed by Pd-NHCs (appended with naphthalimide or hand, their suitability in the Larock heteroannulation
bisnaphthalimide) from o-haloanilines and tertiary was tested by combining 1a (1.0 mmol) with 2a
propargyl alcohols.
In pursuit of effective Pd catalysts for Larock lyst, K2CO3 (2.0 mmol) as base, and TBAB
heteroannulation, new modular Pd-NHCs appended (1.0 mmol) as additive in dioxane at 1208C for 12 h.
(2.0 mmol) in the presence of 1C (0.05 mmol) as cata-
ACHTUNGTRENNUNG
Table 1. Optimization of the catalyst system.[a]
Entry
[Pd]
3aa:4aa[b]
3aa[c,d]
1
2
3
4
5
6
7
8
9
10
–
1C
2C
3C
4C
5C
6C
7C
–
–
30:41
30:42
37:43
34:43
34:44
31:45
30:45
trace:42
trace:38
70
71
77
75
74
73
74
41
37
Pd(OAc)2, PPh3
Pd(OAc)2, 1,10-phen
[a]
Unless otherwise mentioned all the reactions are carried out using 1a (1 mmol), 2a (2 mmol), K2CO3 (2 mmol) as base,
TBAB (1 mmol) as additive and 1,4-dioxane (2 mL) as solvent at 1208C for 8 h.
GC yields using n-decane as internal standard.
[b]
[c]
[d]
Isolated yields.
Addition of acetic acid (0.5 mL) after 8 h of reaction and proceeding for further 6 h.
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Table 2. Scope of bromoanilines.[a]
To our surprise, we have isolated unprecedented het-
eroannulated-dehydrated product 3aa along with 4aa.
Predicitably, there was no reaction in the absence of
a palladium catalyst. Exclusively 4aa was isolated
when K2CO3 (3.5 equiv.) was used in excess. Next, our
prime concern was to generate regioselectively the
dehydrated product 3aa. This was executed by em-
ploying acetic acid, ca. 0.5 mL, to the reaction mix-
ture, astonishingly, all 4aa was converted to 3aa in
6 h. Choosing acid variables like HCl, HBr,
CH3CH2COOH and ClCH2COOH failed to exert any
profound influence in the yield of 3aa. Then, we
screened the catalytic efficacy of 2C–7C (entries 3–8)
and 3C was found to be the best, resulting in isolation
of 3aa in 77% yield (Table 1, entry 4). However, no
enhancement in yield was observed for the reaction
by screening different bases, additives and solvents.
Furthermore, an economic loading (2.5 mol%) of 3C,
6C and 7C showed no profound improvement in the
yield. Eventually, 4.0 mol% loading of 3C was found
to be optimal. For comparison, various palladium cat-
alytic systems – Pd(OAc)2 and PPh3 or Pd(OAc)2 and
1,10-phen were tested with a loading of 5 mol% (en-
tries 9 and 10), invariably none of them are as good
as 3C.[23]
With the optimized reaction conditions in hand, we
then explored the substrate scope with respect to dif-
ferent o-haloanilines. Unsurprisingly, facile reaction
was observed with o-iodo- (81%) or o-bromoanilines
(77%) compared with o-chloroanilines (70%), where-
as o-fluoroanilines demand harsh conditions (1608C
and 48 h) resulting in poor yield (11%). In the cases
of N-acetyl- and N-trifluoroacetyl-o-haloanilines, loss
of protecting group occurred concomitantly with an-
nulation.[12a] Substituents such as Me, OMe, F, CN,
EtOOC, and MeCO at the 4-position were well toler-
ated under the reaction conditions (Table 2).
Gratifyingly, CN, EtOOC and MeCO, well-known
directing groups, did not engage in the C–H activation
process. Furthermore, the fluoro substituent remains
intact during the course of the reaction, i.e., it did not
take part in the cross-coupling reaction. Presumedly,
the use of primary anilines may hamper the yields
owing to the formation of amination by-prod-
[a]
Reaction conditions:
(4 mol%), K2CO3
CH3COOH (0.5 mL), 1,4-dioxane (2 mL) 1208C, isolated
yields.
At 1608C for 48 h.
1
(1 mmol), 2a (2 mmol), 3C
(2 mmol), TBAB (1 mmol),
[b]
ACHTUNGTRENNUNG
ucts[12b,c,24] but, to our amusement, no such attenuation
in yields was observed. N-Functionalized derivatives moderate yields. Remarkably, coupling precursors 2g,
3ha (71%) and 3ia (70%) were obtained with ease. 2m enabled access to structurally unique thiophene-
To further expand the scope of the methodology, containing 2-alkenylindoles 3ag, 3bg and 3am in syn-
we next examined achiral tertiary propargylic alcohols thetically useful yields. More sterically encumbered
as coupling partners (Table 3). Regioselectively, 2-al- naphthyl-containing propargylic alcohols yielded the
kenylindoles 3ab–3ag, 3an, and 3be–3bg as well as 2- desired product 3ad with excellent selectivity. It is
cyclohexenylindoles 3ah–3am and 3bh were successful noteworthy that when 3-ethyl-1-phenylpent-1-yn-3-ol
prepared by adopting the optimized reaction condi- 2n was used, E/Z isomers of 3an were observed in
tions. Both the incorporation of electron-donating a 4:5 ratio.
and electron-withdrawing substitutents was found to
Chiral tertiary propargylic alcohols as reaction part-
be compatible, although some substrates such as 3af ners also worked effectively under standard catalytic
and 3al required longer reaction times to achieve conditions illustrating the broad appilicability of our
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Table 3. Scope of achiral propargylic alcohols.[a]
[a]
Reaction conditions: 1 (1 mmol), 2a (2 mmol), 3C (4 mol%), K2CO3 (2 mmol), TBAB (1 mmol), CH3COOH (0.5 mL),
1,4-dioxane (2 mL) 1208C, isolated yields.
For 24 h.
[b]
[c]
[d]
4:5 (E/Z) ratio.
Determined by H NMR analysis.
1
Pd-NHC-mediated approach (Table 4). The reaction
was also compatible to biphenyl-bearing propargylic
alcohols affording the corresponding highly function-
alised products in good yields. Interestingly, 3-methyl-
1-phenylpent-1-yn-3-ol 5a reacts with 1a to give a Zait-
sevꢂs product 6aa, which was characterized by NMR
spectroscopy. Both 6aa and 6ac show E/Z isomer
ratios of 3:2.
Scheme 1. Gram-scale synthesis of 2-alkenylindole.
To flaunt the effectiveness of this protocol, gram-
scale reactions were carried out (Scheme 1). Under
optimal conditions, reaction of 1a can be scaled up,
affording 3aa without notable erosion in yield and se- respectively (Scheme 2). This was effected by stan-
lectivites.
dard hydrogenation conditions (Pd/C and H2) result-
The synthetic utility of the present methodolgy was ing in the evasive 2-alkyl- and 3-aromatic indoles.[15]
established by transforming 3aa and 6ab to 7a and 7b, Futhermore, p-extended carbazoles 8a and 8b were
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Table 4. Scope of chiral propargylic alcohols.[a]
Scheme 2. Post-synthetic modifications.
Figure 2. Influence of p-additives on the catalytic per-
formance of 3C and 6C. Yields by GC.
[a]
Reaction conditions:
(4 mol%), K2CO3
1
(1 mmol), 2a (2 mmol), 3C
(2 mmol), TBAB (1 mmol),
(Figure 2). Likewise, other additives exhibited re-
duced yields. Furthermore to establish the presence of
the p–p interactions between pyrene and anthracene
with 3C and 6C, UV/Vis absorption studies were car-
ried out in dichloromethane at room temperature.[23]
Increases in the absorption of pyrene and anthracene
CH3COOH (0.5 mL), 1,4-dioxane (2 mL) 1208C, isolated
yields.
[b]
[c]
3:2 (E/Z) ratio.
Determined by H NMR analysis.
1
synthesized by iodine(III)-mediated intramolecular were observed with an increment in concentration of
oxidative arene–alkene coupling reactions.[25]
3C or 6C, which corroborates the formation p–p com-
Recently, Peris and co-workers[18a] demonstrated plexes.
the wise utilization of p-stacking interactions in the
To gain more insight into the reaction mechanism,
homogeneous catalysis: a catalyst bearing a polyaro- we performed a series of experiments (Scheme 3).
matic ring and aromatic reactant engaged in such The formation of 3aa in Scheme 3a is due to the in
non-covalent interactions resulting in enhanced cata- situ generation of HBr which is involved in dehydra-
lytic performance. Correspondingly, to signify the role tion. This hypothesis is further supported by external
of napthalimide and bisnapthalimide in 3C and 6C, addition of CH3COOH (after 8 h) which leads to
respectively, we have introduced good p-stacking ad- complete conversation of 4aa to 3aa (Scheme 3b). Ini-
ditivies such as napthalimide, anthracene and pyrene tial addition of acetic acid resulted in total supression
in the reaction medium and followed the reaction by of oxidative addition (Scheme 3c). Thus, post addition
gas chromatography. Interestingly, anthracene showed of acetic acid is very critical for the formation of de-
a profound influence in the formation of 3aa, i.e., hydrated product 3aa. This is conceived by treatment
a drop of nearly one-fourth in yield was observed of acetic acid to isolated 4aa (Scheme 3d).
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Scheme 3. Preliminary mechanistic studies.
From this discussions, the plausible mechanism has Mechanistic studies to delineate the directional effect
been outlined (Scheme 4). A plausible catalytic cycle of propargyl alcohol and the role of p-stacking are
consistent with these results would involve the initial ongoing.
oxidative addition of C–Br bond to Pd(0) complex to
form NHC-Pd(II)-aryl complex A. Sequential coordi-
nation and selective insertion of tertiary propargylic
alcohol into Pd–C resulted to B. This regioselectivity
was realized by the noticeable directing effect of the
Experimental Section
propargylic OH (see Scheme 4) which substantiates
the Larock regioselective annulation. Intermediate C
Synthesis of Palladium(II)-NHCs (1C–7C)
In air, a vial equipped with a stirring bar was charged with
naphthalimide salts (1L–7L) (1 equiv.), palladium(II) chlo-
ride (1.05 equiv. for 1L–5L and 2.1 equiv. for 6L–7L), K2CO3
(5 equiv. for 1L–5L and 10 equiv. for 6L–7L), and KBr
(3 equiv. for 1L–5L and 6 equiv. for 6L –7L). Pyridine (4 mL
for 1L–5L and 8 mL for 6L–7L) was added and the mixture
stirred at 808C for 16 h. The resulting suspension was cooled
to room temperature, and the solvent was removed under
vacuum. The crude product was purified by column chroma-
tography with DCM/MeOH and precipitated in a dichloro-
was generated by the release of HBr, and eventually
led to 3aa.
In conclusion, we have reported a straightforward,
convenient, and one-pot synthesis of 2-alkenylindoles
catalyzed by Pd-NHCs from o-haloanilines and terti-
ary propargyl alcohols. The present reaction condi-
tions manifest high regioselectivity and excellent sub-
strate scope for both the coupling partners. Appended
naphthalimide or bisnaphthalimide units of the NHC
are found to be crucial for the catalytic process. methane/diethyl ether mixture to give yellow solids.
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Scheme 4. Plausible reaction mechanism.
Synthesis of 2-Alkenylindoles
In a typical run, a sealed tube was charged with o-bromoani-
line (1 mmol), tertiary propargylic alcohol (2 mmol), potassi-
um carbonate (2 mmol), TBAB (1 mmol), 3C (0.04 mmol)
and 1,4-dioxane as solvent (2 mL). The mixture was stirred
at 1208C for 8 h and then 0.5 mL of acetic acid was added
and further heated for another 6 h. After the mixture had
cooled, it was diluted with water (10 mL) and extracted with
DCM (3ꢃ10 mL). The combined organic portions were then
dried over anhydrous sodium sulfate and the solvent was re-
moved completely under vacuum. Isolated yields were ob-
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silica gel using an n-hexane/ether as eluent.
Crystal Structures
CCDC 1512474 (1C), CCDC 1512669 (3C), CCDC 1507686
(3al) and CCDC 1507687 (6ac) contain the supplementary
crystallographic data for this paper. These data can be ob-
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COMMUNICATIONS
Palladium(II)/N-Heterocyclic Carbene-Catalyzed
Regioselective Heteroannulation of Tertiary Propargyl
Alcohols and o-Haloanilines to form 2-Alkenylindoles
9
Adv. Synth. Catal. 2017, 359, 1 – 9
Pradeep Kumar Reddy Panyam, Thirumanavelan Gandhi*
Adv. Synth. Catal. 0000, 000, 0 – 0
9
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!