Friedel-Crafts Hydroxyalkylation of Indoles with α-Keto Amides using Reusable K3PO4/ nBu4NBr Catalytic System in Water

Article abstract of DOI:10.1021/acs.joc.8b00844

A mild and operationally simple Friedel-Crafts hydroxyalkylation of indoles with α-keto amides was developed for the first time by using catalytic amount of K₃PO₄ and nBu₄NBr in water as solvent through a solid-liquid inte

Full text of DOI:10.1021/acs.joc.8b00844

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Article
Friedel-Crafts Hydroxyalkylation of Indoles with #-Keto Amides
using Reusable K3PO4/nBu4NBr Catalytic System in Water
Alagesan Muthukumar, and Govindasamy Sekar
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00844 • Publication Date (Web): 24 Jul 2018
Downloaded from http://pubs.acs.org on July 24, 2018
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FriedelꢀCrafts Hydroxyalkylation of Indoles with αꢀKeto Amides using
Reusable K3PO4/nBu4NBr Catalytic System in Water
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Alagesan Muthukumar and Govindasamy Sekar*
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Department of Chemistry, Indian Institute of Technology Madras, Chennaiꢀ600036,
Tamilnadu, India
ABSTRACT: A mild and operationally simple FriedelꢀCrafts hydroxyalkylation of indoles
with αꢀketo amides is developed for the first time by using catalytic amount of K3PO4 and
nBu4NBr in water as solvent through a solidꢀliquid interface formation. The transitionꢀmetalꢀ
free protocol does not demand column chromatography purification and results in highly pure
indole fused αꢀhydroxy amides in good to excellent yields. Reusability of the catalytic
system up to five cycles and extension to a gramꢀscale reaction are the key advantages of this
1
transformation. The mechanistic study involving HꢀNMR experiments reveal that the
reaction proceeds via ion exchange pathway.
KEYWORDS: Monoindolylation;
αꢀketo amide; reusable catalysts; water solvent;
chromatographyꢀfree
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INTRODUCTION
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Indole core containing molecules are present in many natural products and show biological
activities.1 Derivatives of indole with C3 substitution are generally more attractive for the
construction of pharmaceutically and agriculturally useful molecules, of which 3ꢀindolyl
alcohols play a vital role in organic synthesis as key precursors to synthesize complex
molecules and in pharmaceuticals as drugs.2 Likewise, αꢀhydroxy amides are the important
structural units that exhibit medicinal and pesticidal properties.3 Considering the importance
of 3ꢀindolyl alcohols and αꢀhydroxy amides, the combination of these two units together in a
single molecular framework could be of promising synthetic and biological importance
(Figure 1).
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Figure 1. Target motif bearing of 3ꢀindolyl alcohol and αꢀhydroxy amide units
Selective FriedelꢀCrafts reaction of indole with carbonyl compounds provides a
platform to 3ꢀindolyl alcohols. For instance, monoꢀaddition of indole to aldehyde was
reported using stoichiometric TMSOTf/iꢀPr2NEt4 and Cs2CO3.5 Hydroxyalkylation of indole
with activated keto group of isatin was explored using βꢀcyclodextrin catalyst,6 ureaꢀcholine
chloride deep eutectic solvent,7 DABCOꢀbase ionic liquids,8 bovine pancreas (BPC) enzyme
catalyst9 and chinconaꢀderived squaramide catalyst10 etc. Similarly, trifluoromethyl ketone
was utilized as electrophile for indole hydroxyalkylation using guanidine,11 Cs2CO3,12
dinuclear zinc,13 chincodine catalysts14 and catalystꢀ, solventꢀfree condition.15 In addition,
hydroxyalkylation with αꢀcarbonyl and pyruvate esters was reported using Solkane® 365mfc
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solvent,16 stoichiometric K2CO3
and catalytic SmI2,18 scandium,19 cobalt,20 and
quinine/quinidine systems.21 Based on the literature reports, the mono addition of indole to
carbonyl functionality is limited to few electrophiles. Most of the protocols involved through
the activation of carbonyl group, activation of indole NꢀH bond or deprotection of inꢀsitu
generated silyl ether to form the corresponding 3ꢀindolyl alcohols (Scheme 1aꢀc) which were
meticulously purified by flash chromatography or else it could cause decomposition of the
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products. Thus finding of an alternate protocol with simple purification method is much
desired.
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αꢀKeto amides have recently gained attention among organic chemists as they own
not only biological properties, but also serve as useful synthetic intermediates due to the
presence of potential active sites such as ketone and amide functionalities.22 In this context,
our group has contributed to the functionalization of αꢀketo amides through hydrosilylation
and C(sp3)ꢀH alkylation of 2ꢀalkyl azaarenes.23 Since there is no significant example known
for the fuctionalization of indoles with αꢀketo amides and in connection with our interest in
development of green organic transformations,24 we herein report a first K3PO4/nBu4NBrꢀ
catalyzed hydroxyalkylation of indole with αꢀketo amide in aqueous medium through the
formation of an interface between solid organic and aqueous phases (Scheme 1d). We
intended to use water as the solvent due to the insolubility of αꢀhydroxy amides in water that
makes the purification easier through a simple filtration technique.
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Scheme 1. Hydroxyalkylation of indole
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RESULTS AND DISCUSSION
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The optimization studies were carried out with 0.5 mmol of αꢀketo amide, 2ꢀoxoꢀNꢀ2ꢀ
diphenylacetamide 1a and 0.6 mmol of indole 2a as the model substrates in distilled water
and the results are depicted in Table 1. Initially, 20 mol% of K2CO3 was used as the base
(entry 1). No product formation was observed which can be identified by the resulted yellow
coloured solid reaction mass of unreacted 1a (Figure 2A). From this observation, it is
understood that the reactants remained insoluble in water. Albeit water has many ecological
advantages over other organic solvents,25 the major concern of water mediated reactions is the
solubility of substrates. Thus insolubility of the reactants 1a and 2a in water could be
overcome by the addition of a quaternary ammonium salt in to the reaction mixture which
could form an interface between the solid phase and aqueous phase and thereby assist the
progress of reaction. To our delight, when a combination of 20 mol% of K2CO3 and 20 mol%
of nBu4NBr was tested, it resulted in 81% of the indole addition product, 2ꢀhydroxyꢀ2ꢀ(1Hꢀ
indolꢀ3ꢀyl)ꢀN,2ꢀdiphenylacetamide 3a in 9 h (entry 2). During the course of reaction, the
reactants underwent pasty agglomeration (Figure 2B) which resulted in 3a as white solid
upon vigorous stirring (Figure 2C). The indole fused αꢀhydroxy amide 3a was isolated using
filtration method and confirmed by Xꢀray analysis (CCDC 1569315, see Supporting
Information for detailed crystallography data). The sticky agglomeration of reactants
confirms the formation of an interface between the solid phase and the aqueous phase.
Noteworthy, the reaction failed to proceed only in the presence of 20 mol% of nBu4NBr
(entry 3) and resulted in a yellow oily mass (Figure 2D). Thus, the combination of both base
and quaternary ammonium salt (QAS) is crucial for the progress of reaction.
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When the catalytic loading of nBu4NBr was reduced to 10 mol% and 5 mol% (entries
4 and 5), the reaction with 10 mol% of nBu4NBr gave better yield of 3a. When the activity of
other alkali metal carbonates such as Na2CO3 and Cs2CO3 was tested, the former provided
modest yield and the later failed to produce the product 3a (entries 6 and 7). The use of
hydroxide bases like KOH and NaOH did not improve the reaction yield (entries 8 and 9).
Interestingly, when K3PO4 was used as the base, the reaction yield was increased to 95% and
the reaction time reduced to 4 h (entry 10). But, no significant increase in the yield of 3a was
observed when Na3PO4 was used as the base (entry 11). After screening various bases, K3PO4
was chosen as the catalyst for this transformation.
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Table 1. Optimization of the reaction conditionsa
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Entry
1
Base (mol%)
K2CO3 (20)
K2CO3 (20)
ꢀꢀ
QAS (mol%)
ꢀꢀ
Time (h) Yieldb (%)
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0
81
0
2
nBu4NBr (20)
nBu4NBr (20)
nBu4NBr (10)
nBu4NBr (5)
nBu4NBr (10)
nBu4NBr (10)
nBu4NBr (10)
nBu4NBr (10)
nBu4NBr (10)
nBu4NBr (10)
nBu4NF (10)
nBu4NCl (10)
nBu4NI (10)
nBu4NBr (10)
nBu4NBr (10)
ꢀꢀ
3
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K2CO3 (20)
K2CO3 (20)
Na2CO3 (20)
Cs2CO3 (20)
KOH (20)
83
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0
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81
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95
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95 (92)
84
0
9
NaOH (20)
K3PO4 (20)
Na3PO4•12H2O (20)
K3PO4 (20)
K3PO4 (20)
K3PO4 (20)
K3PO4 (15)
K3PO4 (10)
ꢀꢀ
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aReaction conditions: 1a (0.5 mmol) and 2a (0.6 mmol) in 8 mL of distilled water. In all the
cases, 3a was isolated by simple filtration without further column chromatographic
purification. cYield of 3a in tap water.
b
Screening of other QASs having different halide counter anions such as nBu4NF,
nBu4NCl and nBu4NI, did not provide a better yield as compare to nBu4NBr (entries 12ꢀ14).
When the amount of K3PO4 was reduced to 15 mol%, 95% of 3a was isolated in 8 h (entry
15). Further decrease of the catalyst loading to 10 mol% slowed down the reaction rate and
84% of 3a was isolated in 39 h (entry 16), which suggests that the combination of 15 mol%
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of K3PO4 and 10 mol% of nBu4NBr is suitable catalytic system for this protocol. As
anticipated, no product formation was observed in the absence of both K3PO4 and nBu4NBr
(entry 17).
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Figure 2. Pictorial representations of the reactions having a mixture of (A) 1a, 2a and 20
mol% of base after 24 h. (B) Agglomeration of the reaction mixture in 1ꢀ2 h when 1a, 2a, 20
mol% of base and 20 mol% of QAS were used. (C) Formation of the product 3a after 9 h. (D)
Formation of oily mass after 24 h when 1a, 2a and 20 mol% of QAS were used.
Having the optimized conditions in hand, the scope of the reaction was explored with
different αꢀketo amides and the results are summarized in Table 2. 4ꢀMethyl substituted αꢀ
keto amide gave 83% yield of the corresponding product 3b in 11 h (entry 1). Similarly, αꢀ
keto amide having methoxy group substitution at orthoꢀ, metaꢀ and paraꢀpositions of the
anilide ring provided the corresponding indole fused mandelamides 3c, 3d and 3e in 79%,
73% and 82% yields, respectively (entries 2ꢀ4). 2,6ꢀDimethyl aniline derived αꢀketo amide
resulted in 97% of the indole addition product 3f in 12 h (entry 5). Likewise, αꢀketo amide
tethered to halo substituents such as chloro, bromo and iodo afforded the corresponding
indole bearing αꢀhydroxy amides 3gꢀ3j in 81ꢀ96% yields, respectively (entries 6ꢀ9).
When acetyl and nitro tethered αꢀketo amides were subjected to reaction, the reactants
became sticky mass and further proceeding of the reactions was failed to produce the
corresponding products 3k and 3l (entries 10 and 11). Even when the reactions were
performed in H2O/EtOH mixture, they resulted in no product formation. The reason could be
the deprotonation of αꢀketo amide to form αꢀketo amidate which upon conjugation might
diminish the electrophilicity of ketone. Interestingly, other electron withdrawing groups like
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trifluoromethyl and cyano containing αꢀketo amides underwent smoothly to provide the 3ꢀ
indolyl alcohol analogues 3m and 3n in 83% and 87% yields, respectively (entries 12 and
13). Importantly, aliphatic amine i.e., cyclohexyl amine derived αꢀketo amide also gave the
product 3o in 84% yield (entry 14).
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However, αꢀketo amides with aliphatic ketone failed to provide the corresponding
products 3p and 3s even after 24 h (entries 15 and 18). The inactiveness of the aliphatic αꢀ
keto amides could be either due to the absence of electron withdrawing aryl group or the
presence of enolizable protons alpha to the keto group in basic medium which reduces the
electrophilicity of the keto functionality. Also, the αꢀketo amide bearing methoxy group para
to benzoyl ring underwent reaction smoothly to render the respective product 3q in 80% yield
(entry 16). In addition, 1ꢀnaphthyl amine derived αꢀketo amide provided the corresponding
indole fused αꢀhydroxy amide in 65% yield (entry 17).26
Table 2. Scope of αꢀketo amidea
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aReaction conditions: 1 (0.5 mmol) and 2a (0.6 mmol) in 8 mL of distilled water. bIsolated
yield after purification using filtration. c6:2 ratio of water and ethanol was used.
Next, the scope of indole having different substituents was studied with αꢀketo amide
1a and the results are shown in Table 3. In the case of 5ꢀmethoxy indole, the corresponding
hydroxy alkylated product 4a was isolated in 80% yield in 24 h (entry 1). When 7ꢀethyl
indole was subjected for reaction, it resulted in 81% of the respective product 4b in 24 h
(entry 2). The reaction with sterically demanding 2ꢀmethyl indole proceeded well and
rendered 4c in 87% of yield (entry 3). In addition, indole with halo substitutions such as 5ꢀ
chloro, 6ꢀchloro, 5ꢀbromo and 6ꢀbromo gave the corresponding products 4d, 4e, 4f and 4i in
good yields (entries 4ꢀ6 and 9). Noteworthy, when 1Hꢀpyrrolo[2,3ꢀb]pyridine was utilized,
the mono addition product 4g was isolated in 79% of yield (entry 7). However, the reaction
failed to proceed when weak nucleophilic nitro group substituted indole with was used 4h
(entry 8). Furthermore, when 3ꢀmethyl indole was tested, the reaction failed to provide the C2
addition product 4j (entry 10).
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Table 3. Scope of Indolea
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aReaction conditions: 1a (0.5 mmol) and 2 (0.6 mmol) in 8 mL of distilled water. bIsolated
yield after purification using filtration. c6:2 ratio of water and ethanol was used.
The applicability of other heterocyclic systems such as pyrrole 5, benzimidazole 6,
carbazole 7 and thiazolidineꢀ2,4ꢀdione 8 was tested with αꢀketo amide 1a (Figure 3). But,
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they failed to provide the corresponding products under the standard reaction conditions and
even after enhancing the catalysts loading.27
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N
S
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H
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H
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Figure 3. Reactivity of other heterocycles with αꢀketo amide
Having the successful development of the hydroxyalkylation of indoles with αꢀketo
amides by using K3PO4/nBu4NBr catalysts, next the possibility of recyclability of catalytic
system was investigated using a reaction of 1.0 mmol of αꢀketo amide 1a with 1.2 mmol of
indole 2a using 0.15 mmol of K3PO4 and 0.1 mmol of nBu4NBr in 16 mL of distilled water at
room temperature in 10 h reaction time. After the completion of first cycle, the indole
hydroxyalkylated product 3a was filtered off and the resultant filtrate was recovered and
reused for the successive alkylation reactions. Interestingly, the catalytic system was well
active up to four cycles and furnished 3a in excellent yields. However, in the fifth cycle, the
reaction did not proceed for the complete consumption of starting materials and afforded 61%
of 3a (Figure 4). However, the yield of 3a was increased up to 76% if the reaction time was
prolonged to 48 h.28
Figure 4. Recovery and recyclability of K3PO4/nBu4NBr catalytic system for the
hydroxyalkylation of indole 2a with αꢀketo amide 1a in 10 h reaction time.
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As the activity of the catalytic system diminished in the fifth cycle, we focused on the
investigation of initial reaction kinetics of hydroxyalkylation of indole with αꢀketo amides.
First, the progress of the reaction was monitored and the ratio of disappearance of αꢀketo
amide 1a and the formation of product 3a were determined using HPLC (Figure 5A). The
initial reaction rates were deduced from the experimental curves of 3a concentration versus
reaction time by determination of the slope at the origin. Taking into account of the total
volume of the reaction mixture, the initial rates were then converted into mmol Lꢀ1 minꢀ1
units. The initial reaction rate for the first cycle was found to be 4.54 x 10ꢀ2 mmol Lꢀ1 minꢀ1
(Figure 5B). Whereas, the initial reaction rate for the fifth cycle was found as 2.95 x 10ꢀ2
mmol Lꢀ1 minꢀ1 (Figure 5C). This implies that the catalysts gradually loose the activity in the
fifth cycle.
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A
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Figure 5. A) Plot for the disappearance of 1a and formation of 3a. B) Progress of the
formation of 3a in the first catalytic cycle. C) Progress of the formation of 3a in the fifth
catalytic cycle.
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After exploring the recyclability of catalytic system, the efficiency of FriedelꢀCrafts
reaction was further attempted on a gramꢀscale reaction. For this purpose, 1.13 g (5.0 mmol)
of the αꢀketo amide 1a was subjected to reaction with 0.703 g (6.0 mmol) of indole 2a by
using 0.75 mmol of K3PO4 and 0.5 mmol of nBu4NBr in 50 mL of water at ambient
temperature for 24 h (Scheme 2). The reaction afforded 96 % of the selective addition
product 3a.
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HN
O
K3PO4 (0.75 mmol)
HO
O
O
nBu4NBr (0.5 mmol)
+
HN
HN
H2O (50 mL)
r.t., 24 h, 96%
N
H
1a
1.13 g (5.0 mmol)
3a
1.65 g
2a
0.703 g (6.0 mmol)
Scheme 2. Gramꢀscale reaction
Next, a plausible mechanistic pathway for this transformation is proposed in Scheme
3. Initially, an interaction between nBu4NBr and K3PO4 gave rise to the QAS nBu4N+K2PO4
ꢀ
A.29 It is important to mention that from the optimization study (Table 1, Entries 10 and 11),
it is found that K3PO4 provided better yield than Na3PO4. The observation can be correlated
with Fajan’s rule, that is, as the size of the cation increases, the ionic character of the salt
increases. Thus, the lowered activity of Na3PO4 may be due to less ionic nature than K3PO4
which suppresses the rate of the ion metathesis process.30 Then the QAS A would interact
with indole B through hydrogen bonding to form the adduct C. Then, the adduct C led to the
formation of E up on interaction with αꢀketo amide D. The QAS E would assist the
formation of an interface31 and undergo indolylation of keto group. Formation of CꢀC bond
between C3ꢀposition of indole with αꢀketo amide resulted in QAS F, which further
underwent aromatization of indole ring to form G. Protonation of G would lead to the
formation of the product H by expelling A for the next catalytic cycle.
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Scheme 3. Plausible mechanistic proposal for the hydroxyalkylation of indole with αꢀketo
amide
In order to support our mechanistic hypothesis, the interaction between QAS, base
1
and indole was studied using HꢀNMR experiment in D2O as the solvent and the results are
represented in Figure 6. Initially, the 1HꢀNMR of nBu4NBr was recorded (Figure 6A). Next, a
1:1.5 mixture of nBu4NBr and K3PO4 was stirred in D2O and the resulting solution was
analyzed (Figure 6B). Interestingly, the peaks with respect to nBu4N+ slightly shifted towards
upfield region. This may imply the formation of the intermediate A (Scheme 3) by the
interaction between nBu4NBr and K3PO4. In order to confirm the chemical shift difference,
1
the HꢀNMR for a 1:1.5 mixture of nBu4NBr and KCl was recorded and this resulted in a
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downfield shift (Figure 6C). Moreover, the peaks corresponding to nBu4NCl also appeared
almost in the downfield region (Figure 6D). This implies that the observed chemical shift
changes could be majorly due to the exchange of anions in aqueous medium. Then, a
1:1.5:1.5 combinations of nBu4NBr, K3PO4 and indole were stirred in D2O and the resulting
mixture was analyzed. An upfield shift of peaks corresponding to nBu4N+ was observed
which could be due to the effect of indole ring (Figure 6E). This depicts that the formation of
the adduct C (Scheme 3) might have taken place. In all the cases, the slight shift of peaks
towards upfield or downfield regions indicate the effect of the counter anions32 such as Clꢀ,
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ꢀ
Brꢀ, and K2PO4 with variable electron density which will have different electrostatic
interaction with nBu4N+. Comparing the differences between the chemical shift values of
nBu4N+, the increase of shielding capacities of the anions can be ordered as follows: Clꢀ < Brꢀ
ꢀ
< K2PO4 .
1
Figure 6. H NMR spectra of (A) nBu4NBr (B) nBu4NBr and K3PO4 (C) nBu4NBr and KCl
(D) nBu4NCl (E) nBu4NBr, K3PO4 and indole in D2O with residual solvent peak calibration
at
δ = 4.79 ppm (400 MHz)
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Further evidence to support the mechanistic proposal, a reaction of Nꢀprotected indole
9 was carried out with αꢀketo amide 1a under the standard reaction conditions. It is
noteworthy to mention that the reaction failed to proceed in the absence of indole having free
ꢀNH functionality. This shows that the reaction proceeds through the deprotonation of indole
(Scheme 4A). Next, in order to find out the necessity of free ꢀNH of αꢀketo amide, a reaction
was performed between Nꢀmethyl substituted tertiary αꢀketo amide 11 and indole 2a. The
failure of the reaction implies that the essence of free ꢀNH of αꢀketo amide perhaps due to
interaction with the catalyst33 or to diminish the steric crowding of keto group (Scheme 4B).
In order to understand the importance of amide functionality, a reaction between a nonꢀ
enolizable ketone i.e., benzophenone 13 and indole 2a was carried out (Scheme 4C). The
failure of reaction depicts the role of amide group for enhancing the electrophilicity of the
ketone of αꢀketo amide. Moreover, the development of this FriedelꢀCrafts reaction, biological
activity of the indole fused αꢀhydroxy amides and extension to asymmetric
hydroxyalkylation are under progress.
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Scheme 4. Control experiments
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In conclusion, we have developed an efficient and practical FriedelꢀCrafts hydroxyalkylation
of indoles with αꢀketo amides using inexpensive K3PO4/nBu4NBr in water as the solvent.
Both aromatic and aliphatic amine derived αꢀketo amides were well tolerated and provided
the indole tethered αꢀhydroxy amides in good to excellent yields. It is noteworthy that the
reaction involves simple filtration method by avoiding column chromatography method to
purify the products. The recovery and reusability of the catalytic system was attested up to
five consecutive cycles which denote the process is green and economic. In addition, the
efficacy of the reaction has been further tested with a gramꢀscale reaction. The mechanistic
study shows that the reaction could proceed via the exchange of ions between the base, QAS
and indole which has been demonstrated using the counterion effect in 1HꢀNMR spectroscopy
and control experiments.
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EXPERIMENTAL SECTION
1. General Considerations
All reactions were carried out in ovenꢀdried reaction tubes. Thinꢀlayer chromatography
(TLC) was performed using Merck silica gel 60 F254 preꢀcoated plates (0.25 mm) and
1
visualized by UV fluorescence quenching. H and 13C NMR spectra were recorded on a
1
Bruker 400 and 500 MHz instruments. H NMR spectra were reported relative to residual
DMSO (δ 2.50 ppm) with tetramethylsilane (TMS, δ = 0.00 ppm) as the internal standard. 13C
NMR was reported relative to DMSOꢀd6 (δ = 39.52 ppm). Chemical shifts were reported in
parts per million (ppm) and multiplicities are as indicated: s (singlet), d (doublet), t (triplet), q
(quartet), p (pentet), m (multiplet) and bs (broad singlet). Coupling constants (J) are reported
in Hertz. Melting points were recorded on a Guna capillary melting point apparatus and were
corrected with benzoic acid as reference. Infrared spectra were recorded on a FTIR 4000
Series Spectrometer using dry KBr pellet. The wave numbers of recorded IR signals were
quoted in cmꢀ1. High resolution mass spectra (HRꢀMS) were recorded on QꢀTof Micro mass
spectrometer and 6545 AccurateꢀMass QꢀTof LC/MS instrument. In order to determine the
initial reaction rate, the progress of the reaction was monitored and the ratio of αꢀketo amide
and the product was determined in Shimadzu HPLC systems using Luna® 5 µm Silica (2)
100 Å, LC Column 250 x 4.6 mm.
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CCDCꢀ1569315 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
8
9
Solvents used for extraction and column chromatography were laboratory grade and
used as received. Reaction solvents used were obtained from Fischer Scientific, India Pvt.
Ltd. and Spectrochem Pvt. Ltd. All the anilines were purchased from Alfaꢀaesar, Sigmaꢀ
Aldrich Company, Avra synthesis, Spectrochem Pvt. Ltd. and TCI chemicals. αꢀKeto acids
were purchased from SigmaꢀAldrich Company and Spectrochem Pvt. Ltd. Indoles were
purchased form Spectrochem Pvt. Ltd. and Alfaꢀaesar. K3PO4 was purchased from Sigmaꢀ
Aldrich Company and nBu4NBr was purchased from Spectrochem Pvt. Ltd.
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2. Experimental conditions
2.1 General experimental procedure for synthesis of αꢀketo amides23
To an oven dried RB flask equipped with magnetic bar, benzoyl formic acid (2.0 mmol) in
o
CH2Cl2 (10 mL) was added and the RB flask was cooled to 0 C under nitrogen atmosphere.
Next, triethyl amine (4.0 mmol) was added and stirred for 15 min. Then, thionyl chloride (4.0
mmol) was added drop wise to the reaction mixture and stirring was allowed for 20 min. A
solution of corresponding amine (2.0 mmol) in CH2Cl2 (10 mL) was added slowly to the
o
reaction mixture at 0 C. The stirring was continued at room temperature and the completion
of reaction was monitored by TLC. The reaction mixture was diluted with CH2Cl2 and the
organic layer was washed with water (2 x 20 mL) followed by a saturated aqueous solution of
NaHCO3 (2 x 20 mL) or until no effervescence was observed. The separated organic layer
was washed with water (2 x 20 mL), dried over Na2SO4 and evaporated under reduced
pressure. The pure αꢀketo amide was isolated as solid using silica gel column
chromatography.
2.2 General experimental procedure for FriedelꢀCrafts hydroxyalkylation of indoles
with αꢀketo amides using K3PO4/nBu4NBr Catalytic System
To an oven dried reaction tube equipped a 12mm x 6mm (length x diameter) sized magnetic
bar, 0.5 mmol of αꢀketo amide 1 and 0.6 mmol of indole 2 were added. To which 8 mL water
was added and the reaction was allowed to stir for 5 minutes. Next, 0.075 mmol of K3PO4
and 0.05 mmol of nBu4NBr were added. Initially the reaction mixture underwent
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agglomeration which further allowed for vigorous stirring (if the reaction mixture turned to a
sticky mass, few drops of ethanol can be added for a better stirring) resulted in indole
incorporated αꢀhydroxy amide 3 or 4 formation as a white or offꢀwhite solid. The resulting
residue was filtered through Whatman Filter Paper Grade No. 1ꢀSize 125mm using Büchner
filtrations funnel and washed with hexanes. Further purification using column
chromatography was not required.
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2.3 Spectroscopic and physical data of products
2ꢀHydroxyꢀ2ꢀ(1Hꢀindolꢀ3ꢀyl)ꢀN,2ꢀdiphenylacetamide (3a)
White solid; 154 mg, 90% yield; mp = 174ꢀ176 oC; Rf = (hexanes : ethyl acetate, 70 : 30 v/v);
1H NMR (400 MHz, DMSOꢀd6) δ = 11.03 (bs, 1H), 9.96 (bs, 1H), 7.77 (d, J = 7.6 Hz, 2H),
7.67 (d, J = 7.2 Hz, 2H), 7.24ꢀ7.42 (m, 7H), 7.15 (d, J = 2.4 Hz, 1H), 7.01ꢀ7.11 (m, 2H),
13
6.83ꢀ6.93 (m, 2H); C NMR (100 MHz, DMSOꢀd6) δ = 172.1, 143.5, 138.6, 136.7, 128.6,
127.5, 127.1, 126.8, 125.8, 124.8, 123.6, 121.1, 120.8, 119.9, 118.5, 118.3, 111.5, 77.6; IR
(KBr) ν = 3424, 3340, 3052, 3031, 1666, 1596, 1519, 1434, 1049, 740, 691 cmꢀ1; HRꢀMS
(m/z): [M+Na]+ calcd. for C22H18N2O2Na, 365.1266; found, 365.1265.
2ꢀHydroxyꢀ2ꢀ(1Hꢀindolꢀ3ꢀyl)ꢀ2ꢀphenylꢀNꢀ(pꢀtolyl)acetamide (3b)
White solid; 148 mg, 83% yield; mp = 200ꢀ202 oC; Rf = 0.65 (hexanes : ethyl acetate, 70 : 30
1
v/v); H NMR (400 MHz, DMSOꢀd6) δ = 11.02 (bs, 1H), 9.87 (bs, 1H), 7.57ꢀ7.73 (m, 4H),
7.22ꢀ7.44 (m, 5H), 7.08ꢀ7.18 (m, 3H), 7.05 (t, J = 7.2 Hz, 1H), 6.79ꢀ6.93 (m, 2H), 2.25 (s,
13
3H); C NMR (100 MHz, DMSOꢀd6) δ = 171.9, 143.6, 136.7, 136.0, 132.5, 129.0, 127.5,
127.1, 126.8, 125.8, 124.7, 121.0, 120.8, 119.8, 118.5, 118.4, 111.5, 77.5, 20.5; IR (KBr) ν =
3403, 3329, 3052, 3027, 1663, 1511, 1305, 1168, 1034, 817, 740 cmꢀ1; HRꢀMS (m/z):
[M+Na]+ calcd. for C23H20N2O2Na, 379.1422; found, 379.1433.
2ꢀHydroxyꢀ2ꢀ(1Hꢀindolꢀ3ꢀyl)ꢀNꢀ(2ꢀmethoxyphenyl)ꢀ2ꢀphenylacetamide (3c)
White solid; 147 mg, 79% yield; mp = 206ꢀ208 oC; Rf = 0.42 (hexanes : ethyl acetate, 70 : 30
1
v/v); H NMR (400 MHz, DMSOꢀd6) δ = 11.06 (bs, 1H), 9.94 (bs, 1H), 8.33 (d, J = 8.0 Hz,
1H), 7.64 (d, J = 7.2 Hz, 2H), 7.23ꢀ7.45 (m, 5H), 7.00ꢀ7.20 (m, 5H), 6.82ꢀ6.98 (m, 2H), 3.90
(s, 3H); 13C NMR (100 MHz, DMSOꢀd6) δ = 171.5, 148.1, 143.3, 136.7, 127.6, 127.2, 127.1,
126.8, 125.7, 124.8, 123.8, 121.1, 120.6, 118.6, 118.3, 118.0, 111.6, 110.9, 77.6, 56.0; IR
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(KBr) ν = 3378, 3318, 3115, 3066, 2961, 2834, 1656, 1596, 1526, 1248, 1115, 1034, 740,
695 cmꢀ1; HRꢀMS (m/z): [M+Na]+ calcd. for C23H20N2O3Na, 395.1372; found, 395.1362.
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2ꢀHydroxyꢀ2ꢀ(1Hꢀindolꢀ3ꢀyl)ꢀNꢀ(3ꢀmethoxyphenyl)ꢀ2ꢀphenylacetamide (3d)
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Offꢀwhite solid; 136 mg, 73% yield; mp = 126ꢀ128 oC; Rf = 0.59 (hexanes : ethyl acetate, 70 :
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30 v/v); H NMR (400 MHz, DMSOꢀd6) δ = 11.03 (bs, 1H), 9.94 (bs, 1H), 7.66 (d, J = 7.6
Hz, 2H), 7.49 (s, 1H), 7.24ꢀ7.43 (m, 6H), 7.20 (t, J = 8.0 Hz, 1H), 7.14 (s, 1H), 7.05 (t, J =
7.2 Hz, 1H), 6.82ꢀ6.95 (m, 2H), 6.58ꢀ6.69 (m, 1H), 3.72 (s, 3H); 13C NMR (100 MHz,
DMSOꢀd6) δ = 172.2, 159.5, 143.5, 139.8, 136.7, 129.4, 127.5, 127.1, 126.9, 125.8, 124.8,
121.1, 120.7, 118.5, 118.3, 112.0, 111.5, 109.3, 105.3, 77.6, 55.0; IR (KBr) ν = 3386, 3318,
3059, 2958, 2834, 1670, 1603, 1547, 1027, 838, 754, 695 cmꢀ1; HRꢀMS (m/z): [M+Na]+
calcd. for C23H20N2O3Na, 395.1372; found, 395.1386.
2ꢀHydroxyꢀ2ꢀ(1
H
ꢀindolꢀ3ꢀyl)ꢀ
N
ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀphenylacetamide (3e)
o
White solid; 153 mg, 82% yield; mp = 200ꢀ202 C; Rf = 0.38 (hexanes : ethyl acetate, 70 : 30
1
v/v); H NMR (400 MHz, DMSOꢀd6) δ = 11.01 (bs, 1H), 9.86 (bs, 1H), 7.02ꢀ7.62 (m, 4H),
7.24ꢀ7.41 (m, 5H), 7.13 (d, J = 2.4 Hz, 1H), 7.05 (t, J = 7.4 Hz, 1H), 6.84ꢀ6.92 (m, 3H), 6.80
13
(s, 1H), 3.72 (s, 3H); C NMR (100 MHz, DMSOꢀd6) δ =171.7, 155.5, 143.7, 136.6, 131.7,
127.4, 127.0, 126.8, 125.8, 124.7, 121.4, 121.0, 120.8, 118.5, 118.4, 113.7, 111.5, 77.4, 55.2;
IR (KBr) ν = 3406, 3333, 3059, 2965, 2834, 2824, 2348, 1659, 1515, 1406, 1245, 1042, 831,
751 cmꢀ1; HRꢀMS (m/z): [M+Na]+ calcd. for C23H20N2O3Na, 395.1372; found, 395.1373.
N
ꢀ(2,6ꢀDimethylphenyl)ꢀ2ꢀhydroxyꢀ2ꢀ(1
H
ꢀindolꢀ3ꢀyl)ꢀ2ꢀphenylacetamide (3f)
o
White solid; 180 mg, 97% yield; mp = 210ꢀ212 C; Rf = 0.57 (hexanes : ethyl acetate, 70 : 30
1
v/v); H NMR (400 MHz, DMSOꢀd6) δ = 11.00 (bs, 1H), 9.47 (bs, 1H), 7.67 (d, J = 7.2 Hz,
2H), 7.25ꢀ7.46 (m, 5H), 7.22 (s, 1H), 6.96ꢀ7.11 (m, 4H), 6.88 (t, J = 7.6 Hz, 1H), 6.74 (s,
1H), 2.03 (s, 6H); 13C NMR (100 MHz, DMSOꢀd6) δ = 172.0, 144.0, 136.7, 135.5, 135.2,
127.6, 127.4, 126.9, 126.7, 126.3, 125.9, 124.7, 121.1, 121.0, 118.3, 118.2, 111.4, 77.7, 18.0;
IR (KBr) ν = 3452, 3365, 3249, 3052, 2961, 2915, 1670, 1498, 1091, 768, 743, 698 cmꢀ1;
HRꢀMS (m/z): [M+Na]+ calcd. for C24H22N2O2Na, 393.1579; found, 393.1581.
N
ꢀ(3ꢀChlorophenyl)ꢀ2ꢀhydroxyꢀ2ꢀ(1Hꢀindolꢀ3ꢀyl)ꢀ2ꢀphenylacetamide (3g)
Offꢀwhite solid; 153 mg, 81% yield; mp = 168ꢀ170 oC; Rf = 0.62 (hexanes : ethyl acetate, 70 :
1
30 v/v); H NMR (400 MHz, DMSOꢀd6) δ = 11.04 (bs, 1H), 10.22 (bs, 1H), 8.02 (s, 1H),
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7.59ꢀ7.78 (m, 3H), 7.24ꢀ7.43 (m, 6H), 7.09ꢀ7.18 (m, 2H), 7.05 (t, J = 7.4 Hz, 1H), 6.82ꢀ6.96
(m, 2H); 13C NMR (100 MHz, DMSOꢀd6) δ = 172.7, 143.3, 140.1, 136.7, 133.0, 130.2,
127.5, 127.2, 126.8, 125.8, 124.8, 123.3, 121.1, 120.7, 119.4, 118.6, 118.5, 118.2, 111.5,
77.6; IR (KBr) ν = 3421, 3343, 3129, 3080, 3059, 1659, 1648, 1592, 1526, 1421, 1329, 740,
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695 cmꢀ1; HRꢀMS (m/z): [M+Na]+ calcd. for C22H17N2O2 ClNa, 399.0876; found, 399.0863.
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N
ꢀ(4ꢀChlorophenyl)ꢀ2ꢀhydroxyꢀ2ꢀ(1
H
ꢀindolꢀ3ꢀyl)ꢀ2ꢀphenylacetamide (3h)
o
White solid; 141 mg, 75% yield; mp = 194ꢀ196 C; Rf = 0.63 (hexanes : ethyl acetate, 70 : 30
v/v); 1H NMR (400 MHz, DMSOꢀd6) δ = 11.03 (bs, 1H), 10.15 (bs, 1H), 7.82 (d, J = 8.4 Hz,
2H), 7.65 (d, J = 7.2 Hz, 2H), 7.22ꢀ7.45 (m, 7H), 7.14 (s,1H), 7.05 (t, J = 7.2 Hz, 1H), 6.79ꢀ
13
6.95 (m, 2H); C NMR (100 MHz, DMSOꢀd6) δ = 172.4, 143.4, 137.6, 136.7, 128.5, 127.6,
127.3, 127.2, 126.7, 125.8, 124.8, 121.6, 121.1, 120.8, 118.6, 118.3, 111.6, 77.6; IR (KBr) ν
= 3435, 3326, 3095, 3056, 3027, 1666, 1589, 1511, 1400, 1042, 828, 736 cmꢀ1; HRꢀMS
(m/z): [M+Na]+ calcd. for C22H17N2O2 ClNa, 399.0876; found, 399.0874.
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N
ꢀ(2ꢀBromophenyl)ꢀ2ꢀhydroxyꢀ2ꢀ(1Hꢀindolꢀ3ꢀyl)ꢀ2ꢀphenylacetamide (3i)
White solid; 179 mg, 85% yield; mp = 190ꢀ192 oC; Rf = 0.6 (hexanes : ethyl acetate, 70 : 30
v/v); 1H NMR (400 MHz, DMSOꢀd6) δ = 11.09 (bs, 1H), 10.10 (bs, 1H), 8.30 (d, J = 8.0 Hz,
1H), 7.56ꢀ7.77 (m, 3H), 7.24ꢀ7.47 (m, 7H), 7.18 (s, 1H), 7.06 (t, J = 7.4 Hz, 2H), 6.88 (t, J =
13
7.4 Hz, 1H); C NMR (100 MHz, DMSOꢀd6) δ = 172.0, 142.9, 136.7, 135.6, 132.6, 128.5,
127.7, 127.4, 126.8, 125.7, 125.6, 124.9, 121.2, 121.1, 120.6, 118.7, 117.5, 113.6, 111.6,
77.7; IR (KBr) ν = 3368, 3329, 3112, 3063, 1680, 1586, 1509, 1294, 1031, 751, 695 cmꢀ1;
HRꢀMS (m/z): [M+Na]+ calcd. for C22H17N2O2 BrNa, 443.0371; found, 443.0372.
79
2ꢀHydroxyꢀ2ꢀ(1
H
ꢀindolꢀ3ꢀyl)ꢀ
N
ꢀ(2ꢀiodophenyl)ꢀ2ꢀphenylacetamide (3j)
o
White solid; 224 mg, 96% yield; mp = 184ꢀ186 C; Rf = 0.62 (hexanes : ethyl acetate, 70 : 30
1
v/v); H NMR (400 MHz, DMSOꢀd6) δ = 11.08 (bs, 1H), 9.97 (bs, 1H), 8.19 (d, J = 8.0 Hz,
1H), 7.88 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 7.6 Hz, 2H), 7.24ꢀ7.45 (m, 7H), 7.18 (s, 1H), 7.06
(t, J = 7.6 Hz, 1H), 6.81ꢀ6.96 (two d, J = 7.6, 7.2 Hz, 2H); 13C NMR (100 MHz, DMSOꢀd6) δ
= 172.1, 143.0, 139.0, 138.4, 136.7, 129.0, 127.7, 127.3, 126.8, 126.0, 125.7, 124.9, 121.2,
120.8, 120.7, 118.7, 117.6, 111.6, 90.8, 77.7; IR (KBr) ν = 3382, 3322, 3112, 3059, 1670,
1571, 1519, 1428, 1284, 1034, 761, 701 cmꢀ1; HRꢀMS (m/z): [M+Na]+ calcd. for
C22H17N2O2INa, 491.0232; found, 491.0239.
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2ꢀHydroxyꢀ2ꢀ(1Hꢀindolꢀ3ꢀyl)ꢀ2ꢀphenylꢀNꢀ(4ꢀ(trifluoromethyl)phenyl)acetamide (3m)
4
5
o
White solid; 170 mg, 83% yield; mp = 174ꢀ176 C; Rf = 0.52 (hexanes : ethyl acetate, 70 : 30
v/v); 1H NMR (400 MHz, DMSOꢀd6) δ = 11.05 (bs, 1H), 10.38 (bs,1 H), 8.03(d, J = 8.4 Hz,
2H), 7.59ꢀ7.75 (m, 4H), 7.24ꢀ7.44 (m, 5H), 7.15 (s, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.96 (s,
1H), 6.87 (t, J = 7.4 Hz, 1H); 13C NMR (100 MHz, DMSOꢀd6) δ = 172.9, 143.3, 142.3, 136.7,
127.6, 127.2, 126.9, 125.9 (q, J = 3.0 Hz), 125.8, 124.8, 121.1, 120.7, 120.0, 118.6, 118.1,
111.6, 77.7; IR (KBr) ν = 3438, 3329, 3101, 3059, 3027, 1676, 1515, 1406, 1333, 1171, 845,
743, 691 cmꢀ1; HRꢀMS (m/z): [M+Na]+ calcd. for C23H17N2O2F3Na, 433.1140; found,
433.1137.
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N
ꢀ(2ꢀCyanophenyl)ꢀ2ꢀhydroxyꢀ2ꢀ(1
H
ꢀindolꢀ3ꢀyl)ꢀ2ꢀphenylacetamide (3n)
o
White solid; 160 mg, 87% yield; mp = 184ꢀ186 C; Rf = 0.37 (hexanes : ethyl acetate, 70 : 30
v/v); 1H NMR (400 MHz, DMSOꢀd6) δ = 11.10 (bs, 1H), 10.35 (bs, 1H), 8.00 (d, J = 8.0 Hz,
1H), 7.84 (dd, J = 6.4, 1.4 Hz, 1H), 7.62ꢀ7.72 (m, 3H), 7.26ꢀ7.42 (m, 6H), 7.17ꢀ7.25 (m, 2H),
7.02ꢀ7.10 (m, 1H), 6.84ꢀ6.92 (m, 1H); 13C NMR (100 MHz, DMSOꢀd6) δ = 172.5, 143.0,
140.2, 136.7, 134.1, 133.0, 127.6, 127.4, 126.9, 125.7, 125.04, 124.95, 122.7, 121.2, 120.7,
118.6, 117.6, 116.7, 111.6, 104.9; IR (KBr) ν = 3424, 3322, 3098, 3059, 3031, 2213, 1680,
1575, 1515, 1449, 1294, 1042, 736 cmꢀ1; HRꢀMS (m/z): [M+Na]+ calcd. for C23H17N3O2Na,
390.1218; found, 390.1230.
N
ꢀCyclohexylꢀ2ꢀhydroxyꢀ2ꢀ(1
H
ꢀindolꢀ3ꢀyl)ꢀ2ꢀphenylacetamide (3o)
o
White solid; 146 mg, 84% yield; mp = 182ꢀ184 C; Rf = 0.41 (hexanes : ethyl acetate, 70 : 30
v/v); 1H NMR (400 MHz, DMSOꢀd6) δ = 10.94 (bs, 1H), 7.72 (d, J =8.4 Hz, 1H), 7.57 (d, J =
7.2 Hz, 2H), 7.18ꢀ7.43 (m, 5H), 6.94ꢀ7.11 (m, 2H), 6.86 (t, J = 7.4 Hz, 1H), 6.43 (s, 1H),
3.48ꢀ3.70 (bs, 1H), 1.50ꢀ1.90 (m, 5H), 1.00ꢀ1.45 (m, 5H); 13C NMR (100 MHz, DMSOꢀd6) δ
= 172.1, 144.0, 136.6, 127.3, 126.8, 126.75, 125.8, 124.5, 121.0, 120.9, 118.7, 118.3, 111.4,
77.0, 47.6, 32.4, 32.2, 25.2, 24.6; IR (KBr) ν = 3406, 3322, 3056, 2922, 2849, 1648, 1530,
1034, 747, 701 cmꢀ1; HRꢀMS (m/z): [M+Na]+ calcd. for C22H24N2O2Na, 371.1735; found,
371.1732.
2ꢀHydroxyꢀ2ꢀ(1
H
ꢀindolꢀ3ꢀyl)ꢀ
N
ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀphenylacetamide (3q)
o
White solid; 149 mg, 80% yield; mp = 202ꢀ204 C; Rf = 0.36 (hexanes : ethyl acetate, 70 : 30
v/v); 1H NMR (400 MHz, DMSOꢀd6) δ = 11.01 (d, J = 1.6 Hz, 1H), 9.92 (bs, 1H), 7.75 (d, J
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= 8.0 Hz, 2H), 7.55 (t, J = 8.8 Hz, 2H), 7.36 (t, J = 6.8 Hz, 2H), 7.30 (t, J = 8.0 Hz, 2H), 7.13
(d, J = 2.4 Hz, 1H), 7.01ꢀ7.09 (m, 2H), 6.84ꢀ6.93 (m, 3H), 6.78 (s, 1H), 3.78 (s, 3H); 13C
NMR (100 MHz, DMSOꢀd6) δ = 172.4, 158.4, 138.6, 136.7, 135.6, 128.6, 128.1, 125.8,
124.7, 123.6, 121.0, 120.8, 119.8, 118.53, 118.49, 112.8, 111.5, 77.2, 55.0; IR (KBr) ν =
3378, 3322, 3112, 3066, 2947, 2831, 1663, 1603, 1536, 1515, 1248, 1034, 831, 754, 704 cmꢀ
1; HRꢀMS (m/z): [M+Na]+ calcd. for C23H20N2O3Na, 395.1372; found, 395.1377.
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2ꢀHydroxyꢀ2ꢀ(1
H
ꢀindolꢀ3ꢀyl)ꢀ
N
ꢀ(naphthalenꢀ1ꢀyl)ꢀ2ꢀphenylacetamide (3r)
o
White solid; 128 mg, 65% yield; mp = 183ꢀ185 C; Rf = 0.5 (hexanes : ethyl acetate, 70 : 30
v/v); 1H NMR (500 MHz, DMSOꢀd6) δ = 11.06 (bs, 1H), 10.26 (bs, 1H), 7.95 (d, J = 7.0 Hz,
1H), 7.91 (d, J = 8.2 Hz, 1H), 7.69ꢀ7.87 (m, 4H), 7.28ꢀ7.61 (m, 8H), 7.25 (s, 1H), 7.01ꢀ7.20
13
(m, 2H), 6.90 (t, J = 7.5 Hz, 1H); C NMR (125 MHz, DMSOꢀd6) δ = 172.5, 143.6, 136.7,
133.7, 133.1, 128.3, 127.5, 127.4, 127.1, 126.8, 126.1, 126.08, 125.8, 125.6, 125.1, 124.7,
121.6, 121.1, 120.8, 120.4, 118.5, 118.0, 111.5, 77.9 ; IR (KBr) ν = 3385, 3335, 3136, 3056,
2955, 2842, 1669, 1612, 1516, 1254, 1039, 845, 756, 718 cmꢀ1; HRꢀMS (m/z): [M+Na]+
calcd. for C26H20N2O2Na, 415.1422; found, 415.1437.
2ꢀHydroxyꢀ2ꢀ(5ꢀmethoxyꢀ1Hꢀindolꢀ3ꢀyl)ꢀN,2ꢀdiphenylacetamide (4a)
Offꢀwhite solid; 149 mg, 80% yield; mp = 174ꢀ176 oC; Rf = 0.67 (hexanes : ethyl acetate, 70 :
1
30 v/v); H NMR (400 MHz, DMSOꢀd6) δ = 10.89 (bs, 1H), 9.99 (bs, 1H), 7.77 (d, J = 7.2
Hz, 2H), 7.69 (d, J = 6.8 Hz, 2H), 7.21ꢀ7.42 (m, 6H), 7.00ꢀ7.15 (m, 2H), 6.84 (d, J = 12.0 Hz,
2H), 6.72 (d, J = 8.0 Hz, 1H), 3.55 (s, 3H); 13C NMR (100 MHz, DMSOꢀd6) δ = 172.2, 152.7,
143.4, 138.5, 131.8, 128.6, 127.5, 127.1, 126.9, 126.2, 125.4, 123.6, 119.9, 118.1, 112.1,
110.8, 102.9, 77.5, 55.1; IR (KBr) ν = 3424, 3337, 3316, 3056, 2989, 2939, 2824, 1631,
1533, 1438, 1031, 901, 796, 695 cmꢀ1; HRꢀMS (m/z): [M+Na]+ calcd. for C23H20N2O3Na,
395.1372; found, 395.1372.
2ꢀ(7ꢀEthylꢀ1Hꢀindolꢀ3ꢀyl)ꢀ2ꢀhydroxyꢀN,2ꢀdiphenylacetamide (4b)
White solid; 150 mg, 81% yield; mp = 172ꢀ174 oC; Rf = 0.6 (hexanes : ethyl acetate, 70 : 30
1
v/v); H NMR (400 MHz, DMSOꢀd6) δ = 11.01 (bs, 1H), 9.95 (bs, 1H), 7.76 (d, J = 8.0 Hz,
2H), 7.67 (d, J = 7.2 Hz, 2H), 7.23ꢀ7.39 (m, 5H), 7.19 (d, J = 8.0 Hz, 1H), 7.01ꢀ7.12 (m, 2H),
13
6.75ꢀ6.93 (m, 3H), 2.85 (q, J = 7.6 Hz, 2H), 1.26 (t, J = 7.6 Hz, 3H); C NMR (100 MHz,
DMSOꢀd6) δ = 172.2, 143.5, 138.6, 135.3, 128.7, 127.5, 127.1, 126.92, 126.85, 125.7, 124.4,
123.6, 119.8, 118.9, 118.8, 118.5, 77.6, 23.8, 14.6; IR (KBr) ν = 3421, 3294, 3052, 2965,
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2930, 2862, 1670, 1596, 1526, 1438, 1038, 743, 695 cmꢀ1; HRꢀMS (m/z): [M+Na]+ calcd. for
4
5
C24H22N2O2Na, 393.1579; found, 393.1564.
6
7
2ꢀHydroxyꢀ2ꢀ(2ꢀmethylꢀ1
H
ꢀindolꢀ3ꢀyl)ꢀ
N
,2ꢀdiphenylacetamide (4c)
8
9
o
Pale yellow solid; 155 mg, 87% yield; mp = 194ꢀ196 C; Rf = 0.74 (hexanes : ethyl acetate,
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1
70 : 30 v/v); H NMR (400 MHz, DMSOꢀd6) δ = 10.96 (bs, 1H), 9.99 (bs, 1H), 7.77 (d, J =
8.0 Hz, 2H), 7.71 (d, J = 7.2 Hz, 2H), 7.27ꢀ7.41 (m, 5H), 7.24 (d, J = 8.0 Hz, 1H), 7.07 (t, J =
13
7.2 Hz, 1H), 6.93 (t, J = 7.2 Hz, 1H), 6.62ꢀ6.80 (m, 3H), 2.04 (s, 3H); C NMR (100 MHz,
DMSOꢀd6) δ = 172.5, 144.0, 138.6, 134.7, 134.3, 128.7, 127.52, 127.46, 127.2, 127.1, 123.6,
119.8, 119.7, 118.2, 113.5, 110.3, 77.7, 13.2; IR (KBr) ν = 3414, 3329, 3080, 3063, 3031,
1666, 1592, 1519, 1438, 1160, 1031, 751, 695 cmꢀ1; HRꢀMS (m/z): [M+Na]+ calcd. for
C23H20N2O2Na, 379.1422; found, 379.1425.
2ꢀ(5ꢀChloroꢀ1
H
ꢀindolꢀ3ꢀyl)ꢀ2ꢀhydroxyꢀ
N
,2ꢀdiphenylacetamide (4d)
o
White solid; 139 mg, 74% yield; mp = 174ꢀ176 C; Rf = 0.56 (hexanes : ethyl acetate, 70 : 30
1
v/v); H NMR (400 MHz, DMSOꢀd6) δ = 11.26 (bs, 1H), 9.98 (bs, 1H), 7.76 (d, J = 7.6 Hz,
13
2H), 7.61 (d, J = 7.2 Hz, 2H), 7.25ꢀ7.45 (m, 8H), 7.02ꢀ7.12 (m, 2H), 6.97 (s, 1H); C NMR
(100 MHz, DMSOꢀd6) δ = 172.0, 143.3, 138.5, 135.2, 128.7, 127.7, 127.3, 126.9, 126.8,
126.5, 123.7, 123.1, 121.0, 120.0, 119.9, 118.0, 113.1, 77.5; IR (KBr) ν = 3442, 3340, 3301,
3087, 3059, 3031, 1642, 1596, 1522, 1434, 1305, 1105, 751, 695 cmꢀ1; HRꢀMS (m/z):
[M+Na]+ calcd. for C22H17N2O2 ClNa, 399.0876; found, 399.0878.
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2ꢀ(6ꢀChloroꢀ1Hꢀindolꢀ3ꢀyl)ꢀ2ꢀhydroxyꢀN,2ꢀdiphenylacetamide (4e)
Offꢀwhite solid; 143 mg, 76% yield; mp = 192ꢀ194 oC; Rf = 0.6 (hexanes : ethyl acetate, 70 :
1
30 v/v); H NMR (400 MHz, DMSOꢀd6) δ = 11.17 (bs, 1H), 9.97 (bs, 1H), 7.76 (d, J = 7.6
Hz, 2H), 7.63 (d, J = 7.2 Hz, 2H), 7.43 (s, 1H), 7.15ꢀ7.41 (m, 7H), 7.06 (t, J = 6.8 Hz, 1H),
13
6.85ꢀ7.01 (m, 2H); C NMR (100 MHz, DMSOꢀd6) δ = 172.0, 143.3, 138.5, 137.1, 128.6,
127.6, 127.2, 126.8, 125.9, 124.6, 123.7, 122.1, 119.9, 118.9, 118.5, 111.1, 77.5; IR (KBr) ν
= 3449, 3347, 3308, 3081, 3062, 3038, 1656, 1596, 1530, 1445, 1322, 1231, 1027, 898, 754,
736, 695 cmꢀ1; HRꢀMS (m/z): [M+Na]+ calcd. for C22H17N2O2 ClNa, 399.0876; found,
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399.0868.
2ꢀ(5ꢀBromoꢀ1Hꢀindolꢀ3ꢀyl)ꢀ2ꢀhydroxyꢀN,2ꢀdiphenylacetamide (4f)
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o
White solid; 147 mg, 70% yield; mp = 174ꢀ176 C; Rf = 0.47 (hexanes : ethyl acetate, 70 : 30
4
5
1
v/v); H NMR (400 MHz, DMSOꢀd6) δ = 11.27 (bs, 1H), 9.98 (bs, 1H), 7.76 (d, J = 7.2 Hz,
6
7
8
2H), 7.61 (d, J = 6.4 Hz, 2H), 7.48 (s, 1H), 7.23ꢀ7.43 (m, 7H), 7.17 (d, J = 7.6 Hz, 1H), 7.07
13
(t, J = 6.4 Hz, 1H), 6.98 (s, 1H); C NMR (100 MHz, DMSOꢀd6) δ = 171.9, 143.3, 138.4,
9
135.4, 128.6, 127.7, 127.6, 127.3, 126.8, 126.3, 123.7, 123.5, 123.0, 120.0, 117.9, 113.6,
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111.2, 77.5; IR (KBr) ν = 3442, 3343, 3312, 3091, 3066, 3024, 1642, 1592, 1526, 1449,
1098, 754, 691 cmꢀ1; HRꢀMS (m/z): [M+Na]+ calcd. for C22H17N2O2 BrNa, 443.0371; found,
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443.0369.
2ꢀHydroxyꢀ
N
,2ꢀdiphenylꢀ2ꢀ(1
H
ꢀpyrrolo[2,3ꢀ
b
]pyridinꢀ3ꢀyl)acetamide (4g)
o
White solid; 136 mg, 79% yield; mp = 196ꢀ198 C; Rf = 0.26 (hexanes : ethyl acetate, 50 : 50
v/v); 1H NMR (400 MHz, DMSOꢀd6) δ = 11.61 (bs, 1H), 9.99 (bs, 1H), 8.18 (dd, J = 4.4, 1.2
Hz, 1H), 7.76 (d, J = 7.6 Hz, 2H), 7.65ꢀ7.71 (m, 1H), 7.62 (d, J = 7.2 Hz, 2H), 7.24ꢀ7.40 (m,
6H), 7.07 (t, J = 7.2 Hz, 1H), 7.02 (s, 1H), 6.96 (dd, J = 8.0, 4.4 Hz, 1H); 13C NMR (100
MHz, DMSOꢀd6) δ = 171.9, 148.8, 143.2, 142.6, 138.5, 128.9, 128.6, 127.7, 127.4, 126.8,
124.8, 123.7, 120.0, 118.2, 117.1, 115.2, 77.6; IR (KBr) ν = 3393, 3203, 2992, 2930, 2884,
1670, 1596, 1526, 1442, 1308, 1059, 736 cmꢀ1; HRꢀMS (m/z): [M+Na]+ calcd. for
C21H17N3O2Na, 366.1218; found, 366.1204.
2ꢀ(6ꢀBromoꢀ1
H
ꢀindolꢀ3ꢀyl)ꢀ2ꢀhydroxyꢀ
N,2ꢀdiphenylacetamide (4i)
o
White solid; 156 mg, 74% yield; mp = 191ꢀ193 C; Rf = 0.57 (hexanes : ethyl acetate, 70 : 30
1
v/v); H NMR (400 MHz, DMSOꢀd6) δ = 11.16 (bs, 1H), 9.95 (bs, 1H), 7.75 (d, J = 8.5 Hz,
2H), 7.62 (d, J = 8.2 Hz, 2H), 7.57 (s, 1H), 7.25ꢀ7.37 (m, 6H), 7.23 (s, 1H), 7.00ꢀ7.09 (m,
2H), 6.94 (s, 1H); 13C NMR (100 MHz, DMSOꢀd6) δ = 171.9, 143.3, 138.5, 137.5, 128.6,
127.6, 127.2, 126.8, 125.7, 124.9, 123.6, 122.5, 121.4, 119.9, 118.5, 114.0, 113.9, 77.5; IR
(KBr) ν = 3448, 3356, 3310, 3082, 3064, 3018, 1656, 1599, 1517, 1452, 1010, 746, 695 cmꢀ1;
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HRꢀMS (m/z): [M+Na]+ calcd. for C22H17N2O2 BrNa, 443.0371; found, 443.0372.
2.4 Procedure for recovery and reusability of catalytic system
To an oven dried reaction tube equipped with a magnetic bar, 1.0 mmol of αꢀketo amide 1a,
and 1.2 mmol of indole 2a were weighed. To which 18 mL water was added and the reaction
was allowed to stir for 5 minutes. Next, 0.15 mmol of K3PO4 and 0.1 mmol of nBu4NBr were
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added. After 10 h, the reaction mass was filtered off and resulted in 95% of indole
4
5
incorporated αꢀhydroxy amide 3a. The resulting filtrate was used for next catalytic cycles.
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8
2.5 Determination of initial reaction rate
9
The initial reaction rate of the catalytic cycles has been determined by using HPLC method.
However, we faced a major challenge which was the solubility of reactants. The yellow
colored solid component αꢀketo amide unevenly distributed in the water medium. Thus,
withdrawing of sample was not feasible for every given time interval.
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Hence we carried out separate reactions for the given time interval (each in 0.25
mmol scale of αꢀketo amide 1a 0.3 mmol of indole 2a with 15 mol% of K3PO4 and 10 mol%
of nBu4NBr in 4 mL of distilled water) in order to determine the reaction rate of the first
cycle. The progress of the reactions was monitored through the formation of product 3a using
HPLC method by extracting the reaction mixture with 10 mL of ethyl acetate. 1 mL of the
organic layer was evaporated and dissolved in 4 mL of acetonitrile and from which 5 µL of
sample was injected for HPLC studies.
In the meantime, a bulk reaction of 1.0 mmol scale of αꢀketo amide 1a in 32 mL of
water was carried out. The filtrate received from the fourth catalytic cycle was utilized for the
initial reaction rate studies for the fifth cycle each reaction having 4 mL of water containing
the catalysts (See the ESI for further details).
2.6 Procedure for mechanistic study using 1HꢀNMR spectroscopy
1
Initially, HꢀNMR spectrum for nBu4NBr was recorded. Next, a 1:1.5 mixture of nBu4NBr
and K3PO4 was taken in a reaction tube having D2O solvent. The reaction mixture was stirred
for 1 h and analyzed using 1HꢀNMR spectroscopy. Then, a reaction tube containing a mixture
of nBu4NBr, K3PO4 and indole in 1:1.5:1.5 ratios were stirred in D2O solvent for 1 h, and the
reaction mass was analyzed using 1HꢀNMR spectroscopy (See the ESI for further details).
SUPPORTING INFORMATION
The Supporting Information is available free of charge on the ACS Publications website at
DOI:
Catalyst reusability study, initial reaction rate determination, NMR study, Xꢀray
crystallographic data of 3a, 1H and 13C NMR spectra for all compounds
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AUTHOR INFORMATION
Corresponding Author
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*Eꢀmail: gsekar@iitm.ac.in, Phone: (+91)44ꢀ2257 4229, Fax: (+91)44ꢀ2257ꢀ4202.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
GS thanks IIT Madras for the IRDA project (CHY/17ꢀ18/847/RFIR/GSEK). ALM thanks the
Council of Scientific and Industrial Research (CSIR), New Delhi for the Senior Research
Fellowship.
REFERENCES
1. (a) Humphrey, G. R.; Kuethe, J. T. Practical Methodologies for the Synthesis of Indoles.
Chem. Rev. 2006, 106, 2875ꢀ2911. (b) Bandini, M.; Eichholzer, A. Catalytic
Functionalization of Indoles in a New Dimension. Angew. Chem. Int. Ed. 2009, 48, 9608ꢀ
9644. (c) KochanowskaꢀKaramyan, A. J.; Hamann, M. T. Marine Indole Alkaloids:
Potential New Drug Leads for the Control of Depression and Anxiety. Chem. Rev. 2010,
110, 4489ꢀ4497. (d) Finefield, J. M.; Frisvad, J. C.; Sherman, D. H.; Williams, R. M.
Fungal Origins of the Bicyclo[2.2.2]diazaoctane Ring System of Prenylated Indole
Alkaloids. J. Nat. Prod. 2012, 75, 812ꢀ833.
2. (a) Zhu, S.; Xu, L.; Wang, L.; Xiao, J. Recent Advances in Asymmetric Synthesis of
Optically Active Indole Derivatives from 3ꢀIndolylmethanols. Chin. J. Org. Chem. 2016,
36, 1229ꢀ1240. (b) Kasztelan, A.; Biedrzycki, M.; Kwiatkowskia, P. High‐Pressure‐
Mediated Asymmetric Organocatalytic Hydroxyalkylation of Indoles with
Trifluoromethyl Ketones. Adv. Synth. Catal. 2016, 358, 2962ꢀ2969. (c) Zhang, C.; Zhang,
L.ꢀX.; Qiu, Y.; Xu, B.; Zong, Y.; Guo, Q.ꢀX. Highly Efficient [3+2] Reaction of 3ꢀ
Vinylindoles with 3ꢀIndolylmethanols by BrønstedꢀAcid Catalysis. RSC Adv. 2014, 4,
6916ꢀ6919. (d) Guo, Z.ꢀL.; Xue, J.ꢀH.; Fu, L.ꢀN.; Zhang, S.ꢀE.; Guo, Q.ꢀX. The Direct
Asymmetric Alkylation of αꢀAmino Aldehydes with 3ꢀIndolylmethanols by Enamine
Catalysis. Org. Lett. 2014, 16, 6472ꢀ6475. (e) Xu, B.; Shi, L.ꢀL.; Zhang, Y.ꢀZ.; Wu, Z.ꢀJ.;
Fu, L.ꢀN.; Luo, C.ꢀQ.; Zhang, L.ꢀX.; Penga, Y.ꢀG.; Guo, Q.ꢀX. Catalytic Asymmetric
Direct αꢀAlkylation of Amino Esters by Aldehydes via Imine Activation. Chem. Sci.
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