Catalytic α-Arylation of Imines Leading to N-Unprotected Indoles and Azaindoles

Article abstract of DOI:10.1021/acscatal.6b00040

A palladium N-heterocyclic carbene catalyzed methodology for the synthesis of substituted, N-unprotected indoles and azaindoles is reported. The protocol permits access to various, highly substituted members of these classes of compounds. Although two possible reaction pathways (deprotonative and Heck-like) can be proposed, control experiments, supported by computational studies, point toward a deprotonative mechanism being operative.

Full text of DOI:10.1021/acscatal.6b00040

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Article
Catalytic #-arylation of imines leading to
N-unprotected indoles and azaindoles
Enrico Marelli, Martin Corpet, Yury Minenkov, Rifahath Neyyappadath, Alessandro
Bismuto, Giulia Buccolini, Massimiliano Curcio, Luigi Cavallo, and Steven P. Nolan
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b00040 • Publication Date (Web): 30 Mar 2016
Downloaded from http://pubs.acs.org on March 30, 2016
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ACS Catalysis
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Catalytic α-arylation of imines leading to N-unprotected indoles
and azaindoles
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Enrico Marelli,‡§ Martin Corpet,‡§ Yury Minenkov,¶ Rifahath M. Neyyappadath,§ Alessandro Bis-
muto,§ Giulia Buccolini,§ Massimiliano Curcio,§ Luigi Cavallo¶ and Steven P. Nolan*†#
§ School of Chemistry, EaStCHEM, University of St Andrews, North Haugh, St. Andrews KY16 9ST , U.K.
¶ Physical Sciences and Engineering Division, King Abdullah University of Science and Technology, KAUST Catalysis
Center, Thuwal 23955-6900, Saudi Arabia.
† Chemistry Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
# Department of Inorganic and Physical Chemistry, Universiteit Gent, Krijgslaan 281 - S3, 9000 Ghent, Belgium
ABSTRACT: A Palladium-N-heterocyclic carbene-catalyzed methodology for the synthesis of substituted, N-unprotected
indoles and azaindoles is reported. The protocol permits access to various, highly substituted members of these classes of
compounds. Although two possible reactions pathways (deprotonative and Heck-like) can be proposed, control experi-
ments, supported by computational studies, point towards a deprotonative mechanism being operative.
KEYWORDS: Cross-coupling, NHC, indole, heterocyclic compounds, ketone arylation, ligand effect
yls (AAC) is profoundly influenced by the steric and elec-
INTRODUCTION
tronic properties of the ancillary ligand(s) bound to the Pd
center:8 bulky, electron-rich phosphines, as well as N-
heterocyclic carbenes (NHCs) generally provide state-of-
the-art level of reactivity in cross-coupling processes. 18
Heterocyclic architectures comprise the core of countless
biologically active compounds1 and functional materials.2
The development of methodologies enabling their synthe-
sis, began in the late 19th century,3 remains a field of high
activity. Since the report of early examples by Hegedus,4
Larock5 and Cacchi,6 palladium catalysis has provided a
number of entries into the synthesis and functionalization
of heterocyclic compounds.7 The Pd-catalyzed α-arylation
of carbonyl compounds belongs to the class of deprotona-
tive cross-coupling processes,8 in which the nucleophile is
generated by deprotonation of acidic compounds, afford-
ing the reactive anionic nucleophilic coupling partner. Dis-
covered concomitantly by Hartwig, Buchwald and Miura, 9
it has rapidly evolved and can currently be performed on a
wide range of coupling partners in a very efficient manner.
10
The well known chemistry of carbonyl compounds
makes these protocols particularly suitable for further
11
functionalization towards complex molecules:
indeed,
during the last decade, the application of the α-arylation
(or vinylation) of carbonyl derivatives has provided a
number of protocols achieving highly substituted hetero-
cyclic moieties such as indole derivatives,12 benzofurans,13
isoquinolines14 and pyridines15 (see Scheme 1).
Despite their relatively recent development, these ap-
proaches have already proven useful in the synthesis of
medicinal compounds and natural products, 16 as recently
demonstrated by Donohoe and coworkers in the prepara-
Scheme 1. Selected synthetic approaches leading to highly
substituted heterocycles by αꢀarylation or vinylaton reactions.
tion of various members of the protoberberine class of
17
alkaloids.
As most of the cross-coupling protocols re-
19
Although rare examples of ligand-free protocols exist,
ported to date, the efficiency of the α-arylation of carbon-
our recent work has demonstrated that bulky-yet-flexible,
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“new generation” NHC ligands are ideally suited for this IPr*-derived ligands clearly appears critical in promoting
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palladium catalysis, rendering transformations more facile
and less precious metal demanding. 20 Following this initial
study, we envisaged the possibility of preparing unpro-
tected N-indole derivatives by a sequential ketone aryla-
tion/condensation reaction between a ketone and an o-
chloroaniline derivative. Such an approach would poten-
tially give access to a wide variety of indole scaffolds,
which is considered the most widespread heterocyclic mo-
tif found in industrially relevant compounds.21 Disappoint-
ingly, the intermolecular one-pot approach did not afford
clean reaction crudes, as competition between α-arylation
and N-arylation at the aniline moiety occurs. 22
this reaction efficiently at low catalyst loading. These re-
sults further highlight the colossal effect that exceedingly
bulky, monodentate ligands have on the catalytic proper-
ties of monoligated Pd species.25 Similar performance-
enhancing effects have also been observed under Ni catal-
ysis, both in cross-coupling processes26 and in other trans-
formation types.27 The steric shielding provided by such
ligands has also been used in the study of highly unstable
complexes of coinage metals. 28
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Figure 1. Intramolecular approach towards the unprotected
N-indole scaffold.
In order to overcome this problem, we prepared the imine
1a by condensation of the two coupling partners (see Fig-
ure 1), followed by a distinct cyclization step. A strategy
involving the cyclization of o-haloimines has been previ-
ously developed by Lachance and coworkers,23 although
their protocol suffers many drawbacks (high tempera-
tures, high catalyst loadings, only moderate yields when
chloroarenes are used). Moreover, the reaction conditions
used by this group, namely [Pd(PPh3)4] as catalyst and an
amine base, suggest that a Heck mechanism, rather than
ACC, was active. The present work is therefore aimed at
the development of an intrinsically different, and ideally
more efficient, catalytic method affording indole scaffolds.
RESULTS AND DISCUSSION
Selection of the pre-catalyst: our initial attempts at the
cyclization of 1a were carried out employing the condi-
tions we previously developed for the intramolecular ke-
tone arylation using different precatalysts. 20 We found that
the bulky IPr* ligand (IPr* = [1,3-bis(2,6-dibenzhydryl-4-
methylphenyl)-2-methylene-2,3-dihydro-1H-imidazol-2-
ylidene]) gave full conversion to a single product at 1
mol% catalyst loading. We therefore lowered the catalyst
loading to 0.5% and screened a library of pre-catalyst, var-
ying the bulkiness of the ancillary ligand, the throw-away
ligand and the metal (see Scheme 2). Surprisingly, both
IPr- and IHept-based pre-catalysts (3a and 3c), which
proved active in the α-arylation of ketones,20,24 gave low
conversion. Ni-based pre-catalyst 3f also gave poor con-
versions even at relatively high catalyst loading. We found,
however, that the (flexible) bulkiness of the ligand was
crucial when Pd was the metal: pre-catalysts 3b and 3d,
bearing IPr* and IPr*OMe ligands respectively, afforded
nearly quantitative conversions to the desired product 2a
even at 0.5% catalyst loading; various other ligands gave
unsatisfactory conversion (for the complete screening list,
see ESI). Complex 3e, in which the cinnamyl sacrificial lig-
and was substituted with the acetylacetonate moiety,
showed slightly inferior results. The role of the very bulky
Scheme 2. Selection of the preꢀcatalyst. Conversion deterꢀ
mined by GC analysis. Conditions: 0.25 mmol 1a, 1.1 equiv.
NaOtBu, 0.5 mol% catalyst, 0.125 M in toluene, 110 °C, 16
hours. [a] Catalyst loading 5 mol%.
Optimization of the base/solvent system. Once the
commercially available29 complex 3b was selected as op-
timal pre-catalyst for this transformation, we performed a
screening of base/solvent combinations (selected results
are summarized in Table 1). These experiments showed
the profound influence of the base counterion, especially in
relation with the solvent employed: when using t-butoxide
bases, switching from sodium to lithium to potassium cati-
ons completely changed the reactivity. While NaOtBu gave
good results both in toluene and dioxane, with no detec-
tion of starting material in the latter case (entries 4 and 5),
it gave lower conversion in DME (entry 6). KOtBu gave
high conversion only in toluene, while it performed very
poorly in ethers (entries 7-9); LiOtBu, on the contrary,
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gave almost no conversion in toluene, but high conversion overnight, while tricyclic product 2d required higher cata-
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in ethers, particularly in DME (entries 1-3). Such an influ-
ence of the base counterion is typically observed in depro-
tonative couplings, such as the AAC class of reac-
tions.10b,20,26c The complete base/solvent optimization can
be found in the ESI.
lyst loading and 24 hours under these reaction conditions
to afford good yields. Substitution with 1- and 2-naphthyl
substitution at the 2-position was well tolerated. It is in-
teresting to notice the difference in reactivity observed
between regioisomers 2e and 2f, which only differ in the
position of the indole-naphtalene bond: the former bears
the less sterically crowded 2-naphthalene moiety, and re-
quires longer reaction times when compared to the bulkier
1-naphthalene derivative 2f, clearly showing a positive
effect of the steric pressure on the overall catalytic effi-
ciency. This methodology was also able to afford tetracy-
clic cores such as 2i. Base sensitive functional groups, such
as the nitrile moiety, were tolerated, although in this case
the yield was lower (entry 2j). The presence of a deactivat-
ing electron donating group on the A-ring was also accept-
ed, as exemplified in compound 2k. The protocol was
found suitable for scale up, as illustrated by a 10 mmol-
scale (ca. 2 g) synthesis of 2c, affording slightly improved
yield.
Table 1. Optimization of the base/solvent system.
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Entry
T°C
110
110
110
110
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110
110
110
110
80
Base
Solvent
Toluene
Dioxane
DME
Conversion[a]
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3
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6
7
8
9
LiOtBu
LiOtBu
LiOtBu
NaOtBu
NaOtBu
NaOtBu
KOtBu
KOtBu
KOtBu
NaOtBu
NaOtBu
LiOtBu
KOtBu
NaOtBu
3
81
95
93
>99
68
96
16
33
20
67
33
10
Toluene
Dioxane
DME
Toluene
Dioxane
DME
10
11
12
13
Toluene
Dioxane
DME
80
80
80
Toluene
Dioxane
95b
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15
16
110
110
110
>99c
NaOtBu
NaOtBu
Dioxane
Dioxane
d
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Conditions: Conditions: 0.25 mmol 1a, 1.1 equiv. base, 0.5
mol% 3b, 0.125 M in solvent, 80 °C or 110 °C, 16 hours. [a]
Calculated by GC analysis. [b] Concentration 0.250 M. [c] Reac-
tion time 4 hours. [d] Catalyst loading 0.1%.
The reactions presented in entries 3,4,5, and 7 where re-
peated at lower temperature to identify the best
base/solvent system (entry 11). Further optimization of
the reaction time showed that the conversion was com-
plete after 4 hours (entry 15), and an increase in concen-
tration only slightly lowered the efficiency of this intramo-
lecular process (entry 14). However, a further decrease of
the catalyst loading from 0.5 mol% to 0.1 mol% resulted in
a dramatic decrease in conversion (entry 16). Conditions
summarized in entry 15 were therefore adopted for the
study of the scope of the cyclization reaction.
Scope of the reaction: the protocol proved suitable for the
synthesis of differently substituted indoles (see Scheme 3):
the propiophenone derived imine 1a was fully converted
to the respective 3-methyl-2-phenylindole and isolated in
91% yield. The acetophenone derived indole 2b was also
obtained in good yield under the same conditions. 3-
pentanone-derived indole 2c was also obtained at 0.5
mol% catalyst loading by prolonging the reaction time to
Scheme 3. Scope of the reaction: synthesis of indoles. Condiꢀ
tions: 0.25 mmol 1, 1.1 equiv. NaOtBu, 0.5 mol% or 2.0% 3b,
0.125 M in dioxane, 110 °C, 4ꢀ24 hours. Yields are average of
two runs. [a] Reaction performed on a 10 mmol scale: 10
mmol 1c, 1.2 equiv. NaOtBu, 0.5 mol% 3b, 0.125 M in dioxꢀ
ane, 110 °C, 24 hours.
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Of note, some of the compounds shown in Scheme 3 are kcal/mol, we believe the reaction begins from a complex of
[Pd0(NHC)] with 1,4-dioxane, denoted as 6. The relative
free energy of 6 plus the substrate was taken as 0
kcal/mol. At the first step of the mechanism, reaction of the
organic substrate A with 6 occurs via C–Cl bond scission
and formation of complex 7 and release of dioxane. This
transformation was found to be endergonic by only 1.3
kcal/mol. The following conversion of 7 to 7’ occurs with
hydrogen migration to the nitrogen atom and simultane-
ous coordination of the olefin to the Pd center. This pro-
cess is exergonic by 13.3 kcal/mol. The direct transfor-
mation 6 → 7’ is exergonic by 12 kcal/mol, thus possible if
1 undergoes to isomerization to 1’, which is only 4.3
kcal/mol less stable.
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7
8
industrially significant: compound 2g is a key intermediate
in the synthesis of antidiabetic drugs, while 2i is an in-
termediate in the synthesis of organic electronic materials
31and 2k is used in the synthesis of drugs for lower urinary
tract disfunction.32
30
As it does not require dry box technique, and relies on a
bench-stable, single component pre-catalyst, this protocol
is of remarkable practicality, especially considering the
wide variety of o-chloroaniline and ketones that are com-
mercially available. The results obtained in the synthesis of
indoles encouraged us to extend this methodology to even
more challenging targets, namely 4- and 6-azaindole cores,
which are of great interest in medicinal chemistry (see
Scheme 4). 32
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Starting from species 7’ there are three different pathways
leding to product 2 (or 2’) and regeneration of the catalyst.
First, we propose a pathway involving imine deprotona-
tion followed by reductive elimination (PATH A in Scheme
5). In this mechanism, 7’ reacts with NaOtBu and forms 8’
and NaCl. This step was found endergonic by 11.6
kcal/mol. The following transformation of 8’ into 10’ and
tBuOH was calculated to be thermodynamically favorable
by 22.6 kcal/mol and occurs via transition state TSA1. The
associated Gibbs free energy barrier is 21.1 kcal/mol. 10’
can then eliminate 2’, giving back the catalytic species 6.
This process is exergonic by almost 40 kcal/mol and is
apparently irreversible. Kinetically this is a very fast con-
version since the associated transition state (TSA2) is only
4.3 kcal/mol above 10’. Alternatively, 10’ can isomerize
into 10. This process is thermodynamically favorable by
2.7 kcal/mol. Then, 10 can form the initial species 1 and
eliminate 2 via transition state (TSA3). The process is fa-
vorable thermodynamically by 37.2 kcal/mol and associat-
ed Gibbs free energy barrier is only 3.5 kcal/mol. After-
wards, 2 converts into 2’, since this process is thermody-
namically favorable by 10.8 kcal/mol because of the aro-
matization of the heterocycle. The rate limiting barrier in
PATH A is between TSA1 and 7’ and amounts to 32.7
kcal/mol. Overall 1 → 2’ conversion is exergonic by 62.9
kcal/mol. In addition, direct amine de-protonation of 7’
with NaOtBu to form negatively charged ion 5 with tBuOH
and Na+ species was studied (PATH C). As expected in 1,4-
dioxane solvent, this transformation is thermodynamically
prohibited, being endoergonic by 40.8 kcal/mol, and can
therefore be discarded. The second proposed mechanism
is “Heck-type” (carbopalladation followed by hydride elim-
ination, PATH B) and was postulated for a similar trans-
formation, which occurs under different conditions with
respect to the precatalyst, the base and the temperature
23
Scheme 4. Synthesis of azaindoles. Conditions: 0.25 mmol 1a,
1.1 equiv. NaOtBu, 0.5 or 2.0 mol% 3b, 0.125 M in dioxane,
110 °C, 16ꢀ24 hours. Yields are average of two runs.
Four differently substituted 4-azaindole derivatives were
prepared: compound 5a bearing the bulky 2-naphthyl sub-
stituent at the 2-position, was obtained in good yield. The
propiophenone derivative 5b was obtained in 80% yield
with only 0.5 mol% catalyst loading. Substitution on both
starting material was well tolerated (5c and 5e), and the 6-
azaindole core was also accessible by this methodology
(entry 5d). Attempts to expand the scope to 2,3-diphenyl
substituted indoles, as well as the extension of this meth-
odology to the 5- and 7-azaindole cores, were unsuccess-
ful: in both cases, the synthesis of the imine could not be
achieved in significant yield.
used.
In this mechanism 7’ converts into 11’ via a car-
bopalladation transition state (TSB1). Despite the fact that
this process is thermodynamically favorable by 11.9
kcal/mol, it requires 32.2 kcal/mol of activation energy
that makes it the rate-determining step in PATH B. Further
transformation of 11’ into 12 is exergonic by 16 kcal/mol
and occurs with elimination of 2’. This step is almost barri-
erless since the associated β-hydride elimination transition
state (TSB2) was found to be energetically equal to 11’ (in
fact even slightly more stable which is an artifact of calcu-
lations, due to different basis sets for geometry optimiza-
tions and SP energy evaluations). The subsequent reaction
MECHANISTIC STUDY
Computationlal studies: The proposed mechanisms for
the catalytic transformation of 1 into 2 (or 2’) are given in
Scheme 5. The following notation is introduced in the
scheme: if the substrate is in the enamine form, the com-
pound or complex is designated with a prime (‘), e.g. 1’.
Since coordination of one 1,4-dioxane molecule to
[Pd0(NHC)] species was found to be exergonic by 2.7
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of 12 with NaOtBu to form 13 and NaCl was found to be of 13 into initial catalyst 6 is thermodynamically favorable
1
2
exergonic by 4.7 kcal/mol. The subsequent transformation
by 18.3 kcal/mol and occurs with release of tBuOH.
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2)
45
9
30
TSA1
TSB1
15
ΔG‡=32.2
ΔG‡=40.8
ΔG‡=32.7
7
6+1
8'
0
-15
-30
-45
-60
-75
7'
TSA3
13
10'
11'
10
12
TSB2
ΔG=-62.9
6+2'
Reaction coordinate
Scheme 5. 1) Possible reaction pathways involved in this approach and 2) their representation on the reaction coordinates.
Based on DFT calculations, the catalytic conversion of 1
into 2’ can occur via two highly competitive mechanisms,
PATH A and PATH B. Both mechanisms possess an esti-
mated overall activation barrier of some 33 kcal/mol,
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which is in good agreement with the experimental condi-
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1
2
tions (4 hours at 110 °C in 1,4-dioxane).
Further mechanistic studies: ruling out the Heck
pathway. To shed further light on the mechanism, we
designed an additional set of experiments involving the
use of triethylamine (TEA) as a base for this reaction. Our
hypothesis relies on the intrinsically different role of the
base in the two mechanistic pathways (A and B) pro-
posed: in PATH A, the base is necessary to form the imine
enolate by deprotonation at the α-position, while in
PATH B it acts as a proton sponge, facilitating the reduc-
tion of the Pd(II)-hydride species. In the former case, the
pKa of the base chosen, as well as its counterion, should
play a central role in dictating the catalytic efficiency; in
the latter case, the reactivity should not significantly be
affected by the pKa of the base. This hypothesis is based
on typical conditions for the Heck reaction compared to
those employed for the AAC.33 The use of TEA would
therefore be disadvantageous if the reaction proceeds
through PATH A, in which the deprotonation step is rate-
determining, while it would not affect the reaction out-
come in PATH B, as in that case the base is not involved
in the rate-limiting step. The catalytic experiments per-
formed are showed in Scheme 6. The reaction summa-
rized in eq. 1 was performed under the conditions previ-
ously applied for the transformation (see Scheme 3, entry
2a) substituting the t-butoxide base with TEA, and af-
forded no detectable product.
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Scheme 7. Three additional reactions used to discrimi-
nate between PATH A and PATH B.
The reaction depicted in eq. 1 of Scheme 7 was found
thermodynamically unfavorable by 4.1 kcal/mol. Clearly,
with standard 1 M conditions the reactants are more
preferable than the products. However, this equilibrium
can be shifted to the left by the concentration factor, and
is therefore theoretically possible. The second reaction
(eq. 2) is thermodynamically forbidden since the associ-
ated Gibbs free energy change is 16.1 kcal/mol: this equi-
librium cannot be shifted by the concentration factor.
Finally, the direct α-deprotonation showed in eq. 3 can-
not take place under the computed conditions, as the
products are immediately converted to the starting ma-
terials. Comparing these computed results with the ex-
periments performed using TEA as a base (Scheme 6), we
can conclude that the Heck-like mechanism, that would
be theoretically active in the presence of a weak base, can
be excluded as a viable reaction route. Therefore, we
propose that the reaction proceeds via a deprotonative
mechanism, related to that of the α-arylation of carbon-
yls, when [Pd(IPr*)(cinnamyl)Cl] (3b) is used as pre-
catalyst.
CONCLUSIONS
The present work disclosed an efficient synthesis of N-
unprotected indole derivatives starting from o-
chloroarylimines. This transformation highlights the re-
markable effects of the steric properties of the ligand
employed, and allows for the synthesis of a wide variety
of functionalized compounds also on a gram scale. This
protocol represents an improvement over existing meth-
ods in terms reaction temperature, catalyst loading, av-
erage yields and reaction scope. Other catalytic protocols
leading to the synthesis and functionalization of hetero-
cycles are currently being developed in our laboratories
and will be reported in due course.
Scheme 6. Further mechanistic studies
To rule out the possibility that this could be due to the
inability of such a weak base to promote the activation of
34
the cinnamyl-based pre-catalyst , we performed a reac-
tion under the same conditions, adding 10 mol% of
NaOtBu. In this case, only 10% conversion was observed
(eq. 2). We finally tested the feasibility of such a reaction
under more forcing conditions, increasing the catalyst
loading to 2.0 mol% and the reaction time to 24 hr, ob-
taining again only 10% conversion (eq. 3). These results
point towards an AAC-like mechanism (PATH A) rather
than a Heck mechanism. To further confirm these data,
additional computational experiments were performed,
examining the thermodynamic feasibility of the catalytic
steps involving the base in both PATH A and PATH B.
EXPERIMENTAL SECTION
EXPERIMENTAL DETAILS
Synthesis of imines 1 and 4 : METHOD A: The ketone (2.0
mmol, 1.0 equiv.), 2-chloroaniline (2.4 mmol, 1.2 equiv.) NaH-
CO3 (840 mg, 10 mmol, 5 equiv.), a magnetic bar and activated
molecular sieves were charged with 8 mL of toluene into a 50
mL Schlenk flask under anaerobic/anhydrous conditions. The
reaction was then stirred for 16 hr at 90°C. After this time the
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mixture was permitted to cool to room temperature and filtered
[Pd(IPr*)(cinnamyl)Cl] 3b (55 mg, 0.5 mol%) was dissolved in 5
mL of dioxane and added to the reaction mixture with a syringe,
washing with 5 mL dioxane. The flask was then immerged in a
pre-heated oil bath at 110°C, stirring at 300 rpm for 24 hours.
The reactor was then permitted to cool to rt and the reaction
quenched with 20 mL of water and extracted with diethyl ether
(4 x 20 mL). The combined organic layers where dried over
MgSO4, filtered and evaporated under vacuum. The crude was
left under high vacuum for two hours, after which time NMR
analysis revealed the pure product to be present (>95 %). Iso-
lated yield 1.31 g, 83%.
though celite, the solvent and the excess aniline were evapo-
rated under reduced pressure. The imine isolated was used
without further purification. METHOD B: The ketone (2.0 mmol,
1.0 equiv.), 2-chloroaniline (2.4 mmol, 1.2 equiv.) p-toluene-
sulfonic acid monohydrate (38 mg, 0.2 mmol, 10%) a magnetic
stiring bar and activated molecular were charged with 10 mL of
toluene into a 50 mL Schlenk flask under anhydrous conditions.
The reaction was then stirred for 16 hr at 110°C. After this time
the mixture was permitted to reach room temperature and was
then quenched with sodium carbonate, filtered though celite,
the solvent and the excess aniline were evaporated under re-
duced pressure. The imine was used without further purifica-
tion.
LARGE SCALE SYNTHESIS OF 1c: A flame-dried 100 mL
round bottom flask, equipped with a stirring bar and a conden-
ser, was charged with 30 g of activated 3Å molecular sieves,
21.2 mL of 3-pentanone (17. 3 g, 0.2 mol, 10 equiv.) and 2.1 mL
of 2-chloroaniline (2.51 g, 20 mmol). The mixture was heated to
reflux for 48 hours, then allowed to cool to rt and filtered
through MgSO4, washing with EtOAc, then the excess pentanone
was evaporated using a rotoevaporator and the traces of 2-
chloroaniline removed leaving the mixture drying at the pump
for two days at 35 °C with stirring. The desired product was
obtained as a yellow liquid (2.5 g, 64%)
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COMPUTATIONAL DETAILS.
Geometry optimizations and calculations of thermo-
chemical corrections. All geometry optimization were per-
formed using the PBE GGA35 functional as implemented in
36
PRIRODA 13 DFT code. All electron basis sets (λ1) 37 compa-
rable in quality to the correlation consistent valence double-ζ
plus polarization (cc-PVDZ) basis sets of Dunning were used. All
stationary geometries were characterized by analytically calcu-
lated Hessian matrix. Scalar relativistic effects (for Pd, Br) were
38
taken into account via the Dyall Hamiltonian
The default,
adaptively generated PRIRODA grid, corresponding to an accu-
racy of the exchange-correlation energy per atom (1×10-8 har-
tree) was decreased by a factor of 100 for more accurate evalua-
tion of the exchange-correlation energy. Default values were
used for the Self-Consistent-Field (SCF) convergence and the
maximum gradient for geometry optimization criterion (1×10-4
au), whereas the maximum displacement geometry conver-
gence criterion was decreased to 0.0018 au. Translational, rota-
tional, and vibrational partition functions for thermal correc-
tions to arrive at total Gibbs free energies were computed with-
in the ideal-gas, rigid-rotor, and harmonic oscillator approxima-
tions. The temperature used in the calculations of thermochem-
ical corrections was set to 298.15 K in all the cases.
Optimized protocol for the cyclization of imines into in-
doles:
METHOD Cy-A: The pre-catalysts 3b [Pd(IPr*)(cinnamyl)Cl]
(1.5 mg, 0.5 mol%), the imine (0.25 mmol, 1 equiv.) and NaOtBu
(26.4 mg, 0.28 mmol, 1.1 equiv) were weighted and charged
into a screw-cap vial equipped with a magnetic stirring bar. The
vial was closed with a septum cap and purged with 3 va-
cuum/nitrogen cycles. Dry dioxane (2 mL) was added with a
syringe, and the reaction was then stirred at 110°C for 4 hr. The
vessel was then allowed to cool to rt and the reaction was
quenched with 3 drops of water, the organic phase was filtered
through magnesium sulfate washing with ethyl acetate. The two
reaction duplicates were purified together via flash chromato-
graphy to afford the pure product.
METHOD Cy-B: The precatalysts 3b [Pd(IPr*)(cinnamyl)Cl]
(1.6 mg, 0.5 mol%), the imine (0.25 mmol, 1 equiv.) and NaOtBu
(26.4 mg, 0.28 mmol, 1.1 equiv) were weighted in a screw-cap
vial equipped with a magnetic stirring bar. The vial was closed
with a septum cap and purged with 3 vacuum/nitrogen cycles.
Dry dioxane (2 mL) was added by syringe, and the reaction was
then stirred at 110°C for 16 hr. The vessel was then allowed to
cool to rt and the reaction quenched with 3 drops of water, the
organic phase was filtered through magnesium sulfate washing
with ethyl acetate. The two reactions duplicate were purified
together via flash chromatography to afford the desired pro-
duct.
METHOD Cy-C: The pre-catalysts 3b [Pd(IPr*)(cinnamyl)Cl]
(5.9 mg, 2.0%), the imine (0.25 mmol, 1 equiv.) and NaOtBu
(26.4 mg, 0.28 mmol, 1.1 equiv) were weighted in a screw-cap
vial equipped with a magnetic stirring bar. The vial was closed
with a septum cap and purged with 3 vacuum/nitrogen cycles.
Dry dioxane (2 mL) was added with a syringe, and the reaction
was then stirred at 110°C for 24 hr. The vessel was then allowed
to cool to rt and the reaction was quenched with 3 drops of wa-
ter, the organic phase was filtered through magnesium sulfate
washing with ethyl acetate. The two reactions duplicate were
purified together via flash chromatography to afford the desired
product.
LARGE SCALE CYCLIZATION: A flame dried 250 mL Schlenk
flask containing a stirring bar was charged with NaOtBu (1.15 g,
12 mmol, 1.2 equiv.), filled with argon and then 60 mL of dry,
degassed dioxane were added via syringe. The imine (1.95 g, 10
mmol) was weighed into a vial and added via syringe, washing
both vial and syringe with dioxane (2x5 mL).
Single-point (SP) energy evaluations. The energies were
39
re-evaluated at optimized geometries by means M06
func-
40
tional as implemented in Gaussian 09 code. All electron def2-
tzvpp basis sets of Ahlrichs groups were used with correspond-
ing density-fitting basis sets. 41 The default value for the SP SCF
convergence was adopted. The “Integral (grid=ultrafine)” option
was used for evaluation of the exchange-correlation term.
Solvent effects. Electrostatic and non-electrostatic solvent
42
effects were estimated by means of SMD solvation model as
implemented in Gaussian 09 code. The internal program values
for 1,4-Dioxane (dielectric constant, etc.) were adopted.
ASSOCIATED CONTENT
Supporting Information
Supporting information available: experimental procedure,
computational details and characterization of the products.
This material is available free of charge via the internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* Prof. Dr. Steven P. Nolan: steven.nolan@ugent.be
Author Contributions
All authors have given approval to the final version of the
manuscript. ‡EM and MC contributed equally to this work.
ACKNOWLEDGMENTS
We thank Dr. Josè A. Fèrnandez-Sàlas, Dr. Fady Nahra, and
Dr. Marcel Brill for useful discussions. Dr. Sunil V. Sharma,
Dr. Cristina Pubil and Dr. Rebecca J. M. Goss are gratefully
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Page 8 of 10
acknowledged for the help provided during the revision of
Kelley, S. P.; Rogers, R. D.; Shaughnessy, K. H. Eur. J.
1
2
3
4
5
6
this manuscript. We thank ERC (FUNCAT to SPN) for fund-
ing. We thank the EPSRC NMSSC in Swansea for mass spec-
trometric analyses. The EPSRC is gratefully acknowledged
for financial support (Ph.D. studentships to AB, GB, MC and
RMN Through the doctoral training centre CRITICAT
EP/L016419/1).
Org. Chem. 2014, 2014, 7395–7404; j) DeAngelis, A. J.;
Gildner, P. G.; Chow, R.; Colacot, T. J. J. Org. Chem.
2015, 80, 6794–6813.
(11) Potukuchi, H. K.; Spork, A. P.; Donohoe, T. J. Org.
Biomol. Chem. 2015, 13, 4367–4373.
7
8
9
(12) a) Rutherford, J. L.; Rainka, M. P.; Buchwald, S. L.
J. Am. Chem. Soc. 2002, 124, 15168–15169; b) Bar-
luenga, J.; Jiménez-Aquino, A.; Valdés, C.; Aznar, F.
Angew. Chem. Int. Ed. 2007, 46, 1529–1532; c) Bar-
luenga, J.; Jiménez-Aquino, A.; Aznar, F.; Valdés, C. J.
Am. Chem. Soc. 2009, 131, 4031–4041; d) Hellal, M.;
Singh, S.; Cuny, G. D. J. Org. Chem. 2012, 77, 4123–
4130.; e) Knapp, J. M.; Zhu, J. S.; Tantillo, D. J.; Kurth,
M. J. Angew. Chem. Int. Ed. 2012, 51, 10588–10591; f)
Rotta-Loria, N. L.; Borzenko, A.; Alsabeh, P. G.;
Lavery, C. B.; Stradiotto, M. Adv. Synth. Catal. 2015,
357, 100–106; g) Pham, N. N.; Dang, T. T.; Ngo, N. T.;
Villinger, A.; Ehlers, P.; Langer, P. Org. Biomol. Chem.
2015, 13, 6047–6058.
ABBREVIATIONS
AAC, alpha arylation of carbonyls; NHC, N-heterocyclic car-
bene; TEA, tryethylamine.
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REFERENCES
(1) a) Horton, D. A.; Bourne, G. T.; Smythe, M. L.
Chem. Rev. 2003, 103, 893–930; b) Galliford, C. V;
Scheidt, K. A. Angew. Chem. Int. Ed. 2007, 46, 8748–
8758; c) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435–
446; d) Michael, J. P. Nat. Prod. Rep. 2005, 22, 627–
646.
(2) Hughes, G.; Bryce, M. R. J. Mater. Chem. 2005, 15,
94–107.
(3) a) Knorr, L. Chem. Ber. 1884, 17, 1635–1642; b)
Fischer, E.; Hutz, H. Chem Ber. 1895, 28, 585-587.
(13) a) Eidamshaus, C.; Burch, J. D. Org. Lett. 2008,
10, 4211–4214. b) Lee, J. H.; Kim, M.; Kim, I. J. Org.
Chem. 2014, 79, 6153–6163.
(4) Hegedus, L. S.; Mulhern, T. A.; Mori, A. J. Org.
Chem. 1985, 50, 4282–4288.
(14) a) Donohoe, T. J.; Pilgrim, B. S.; Jones, G. R.; Bas-
suto, J. a. Proc. Natl. Acad. Sci. U. S. A. 2012, 109,
11605–11608; b) Pilgrim, B. S.; Gatland, A. E.; McTer-
nan, C. T.; Procopiou, P. A.; Donohoe, T. J. Org. Lett.
2013, 15, 6190–6193.
(5) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991,
113, 6689–6690.
(6) Arcadi, A.; Cacchi, S.; Marinelli, F. Tetrahedron
Lett. 1992, 33, 3915–3918.
(7) a) Zeni, G.; Larock, R. C. Chem. Rev. 2006, 106,
4644–4680; b) D’Souza, D. M.; Muller, T. J. J. Chem.
Soc. Rev. 2007, 36, 1095–1108; c) Platon, M.; Amardeil,
R.; Djakovitch, L.; Hierso, J.-C. Chem. Soc. Rev. 2012,
41, 3929–3968; d) Wu, X.-F.; Neumann, H.; Beller, M.
Chem. Rev. 2013, 113, 1–35.
(15) Hardegger, L. A.; Habegger, J.; Donohoe, T. J.
Org. Lett. 2015, 17, 3222–3225.
(16) Sivanandan, S. T.; Shaji, A.; Ibnusaud, I.;
Seechurn, C. C. C. J.; Colacot, T. J. Eur. J. Org. Chem.
2015, 2015, 38–49.
(17) Gatland, A. E.; Pilgrim, B. S.; Procopiou, P. A.;
Donohoe, T. J. Angew. Chem. Int. Ed. 2014, 53, 14555–
14558.
(8) Johansson, C. C. C.; Colacot, T. J. Angew. Chem.
Int. Ed. 2010, 49, 676–707.
(9) a) Satoh, T.; Kawamura, Y.; Miura, M.; Nomura,
M. Angew. Chem. Int. Ed. 1997, 36, 1740–1742; b)
Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997,
119, 11108–11109; c) Hamann, B. C.; Hartwig, J. F. J. Am.
Chem. Soc. 1997, 119, 12382–12383.
(18) a) Marion, N.; Nolan, S. P. Acc. Chem. Res. 2008,
41, 1440–1449; b) Fortman, G. C.; Nolan, S. P. Chem.
Soc. Rev. 2011, 40, 5151–5169; c) Lundgren, R. J.; Stra-
diotto, M. Chem. Eur. J. 2012, 18, 9758–9769.
(19) a) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S.
L. J. Am. Chem. Soc. 2000, 122, 1360–1370; b) Carole,
W. A.; Bradley, J.; Sarwar, M.; Colacot, T. J. Org. Lett.
2015, 17, 5472–5475.
(10) For selected reports on the arylation of carbonyl
compounds, see: a) Martín, R.; Buchwald, S. L. An-
gew. Chem. Int. Ed. 2007, 46, 7236–7239; b) Grasa, G.
A.; Colacot, T. J. Org. Lett. 2007, 9, 5489–5492; c)
Grasa, G. A.; Colacot, T. J. Org. Process Res. Dev.
2008, 12, 522–529; d) Biscoe, M. R.; Buchwald, S. L.
Org. Lett. 2009, 11, 1773–1775; e) Hesp, K. D.;
Lundgren, R. J.; Stradiotto, M. J. Am. Chem. Soc. 2011,
133, 5194–5197; f) Johansson Seechurn, C. C. C.;
Parisel, S. L.; Colacot, T. J. J. Org. Chem. 2011, 76,
7918–7932; g) Crawford, S. M.; Alsabeh, P. G.; Stra-
diotto, M. Eur. J. Org. Chem. 2012, 2012, 6042–6050;
h) Zheng, B.; Jia, T.; Walsh, P. J. Org. Lett. 2013, 15,
4190–4193; i) Raders, S. M.; Jones, J. M.; Semmes, J. G.;
(20) Marelli, E.; Corpet, M.; Davies, S. R.; Nolan, S. P.
Chem. Eur. J. 2014, 20, 17272–17276.
(21) a) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105,
2873–2920; b) Platon, M.; Amardeil, R.; Djakovitch,
L.; Hierso, J.C. Chem. Soc. Rev. 2012, 41, 3929–3968.
(22) This approach has been successfully used by
Spergel and coworkers, although their protocol has
major drawbacks regarding substrate scope (only
electron poor aniline derivatives) and efficiency (20%
loading of a well-defined Pd-NHC complex was nec-
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essary to reach generally moderate yields): a) Spergel, (34) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev.
1
2
3
4
5
6
7
8
S. H.; Okoro, D. R.; Pitts, W. J. Org. Chem. 2010, 75,
5316–5319. A complementary method for the synthesis
of 2-vinyl, N-unprotected indoles and carbazoles has
been recently reported by Kapur and coworkers: b)
Kale, A. P.; Kumar, G. S.; Mangadan, A. R. K.; Kapur,
M. Org. Lett. 2015, 17, 1324-1327.
2000, 100, 3009–3066. See also conditions reported in
ref. 22.
(35) a) Marion, N.; Navarro, O.; Mei, J.; Stevens, E. D.;
Scott, N. M.; Nolan, S. P. J. Am. Chem. Soc. 2006, 128,
4101–4111; b) Hruszkewycz, D. P.; Balcells, D.; Guard,
L. M.; Hazari, N.; Tilset, M. J. Am. Chem. Soc. 2014,
136, 7300–7316; c) Takeda, Y.; Ikeda, Y.; Kuroda, A.;
Tanaka, S.; Minakata, S. J. Am. Chem. Soc. 2014, 136,
8544–8547.
(23) Lachance, N.; April, M.; Joly, M.-A. Synthesis
2005, 2571–2577. Together with the works in ref. 22,
this is the only Pd-catalyzed protocol affording N-
unprotected indoles to our knowledge.
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42
43
44
45
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
(36) a) Perdew, J. P.; Burke, K.; Ernzerhof, M. Phys.
Rev. Lett. 1997, 78, 1396-1396; b) Perdew, J. P.; Burke,
K.; Ernzerhof, M. Phys. Rev. Lett. 1996, 77, 3865-3868.
(24) Marion, N.; Ecarnot, E. C.; Navarro, O.; Amoro-
so, D.; Bell, A.; Nolan, S. P. J. Org. Chem. 2006, 71,
3816–3821.
(37) Laikov, D. N.; Ustynyuk, Y. A. Russ. Chem. Bull.
2005, 54, 820-826.
(25) a) Szilvási, T.; Veszprémi, T. ACS Catal. 2013, 3,
1984–1991; b) Izquierdo, F.; Manzini, S.; Nolan, S. P.
Chem. Commun. 2014, 50, 14926–14937.
(38) Laikov, D. N. Chem. Phys. Lett. 2005, 416, 116-120.
(39) Dyall, K. G. Chem. Phys. Lett. 1994, 224, 186-194.
(26) a) Martin, A. R.; Makida, Y.; Meiries, S.; Slawin,
A. M. Z.; Nolan, S. P. Organometallics 2013, 32, 6265–
6270; b) Martin, A. R.; Nelson, D. J.; Meiries, S.;
Slawin, A. M. Z.; Nolan, S. P. Eur. J. Org. Chem. 2014,
3127–3131; c) Fernández-Salas, J. A.; Marelli, E.;
Cordes, D. B.; Slawin, A. M. Z.; Nolan, S. P. Chem.
Eur. J. 2015, 21, 3906–3909; d) Marelli, E.; Fernández
Salas, J. A.; Nolan, S. P. Synthesis 2015, 47, 2032–2037.
(40) Zhao, Y.; Truhlar, D. Theor. Chem. Acc. 2008,
120, 215-241.
(41) Gaussian 09, Revision D.01, Frisch, M. J.; Trucks,
G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A. ;
Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci,
B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.
; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng,
G.; Sonnenberg, J. L.; Hada, M.; Ehara, M; Toyota, K.;
Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.;
Honda, T.; Kitao, O.; Nakai, H.; Vreven, T.; Mont-
gomery, J. A. Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark,
M.; Heyd, J. J; Brothers, E.; Kudin, K. N.; Staroverov,
V. N.; Kobayashi, R.; Normand, J.; K. Raghavachari,
A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, Cossi,
M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.;
Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A.
J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R.
L.; Morokuma, R.; Zakrzewski, V. G.; Voth, G. A.; Sal-
vador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A.
D.; Farkas, Ö.; Foresman, J. B.; Ortiz, J. V.;
Cioslowski, J.; and Fox, D. J. Gaussian, Inc., Walling-
ford CT, 2009.
(27) a) Makida, Y.; Marelli, E.; Slawin, A. M. Z.; Nolan,
S. P. Chem. Commun. 2014, 50, 8010–8013; b)
Schramm, Y.; Takeuchi, M.; Semba, K.; Nakao, Y.;
Hartwig, J. F. J. Am. Chem. Soc. 2015, 137, 12215–12218.
(28) a) Hussong, M. W.; Rominger, F.; Krämer, P.;
Straub, B. F. Angew. Chem. Int. Ed. 2014, 53, 9372–
9375; b) Hussong, M. W.; Hoffmeister, W. T.;
Rominger, F.; Straub, B. F. Angew. Chem. Int. Ed.
2015, 54, 10331–10335.
(29) Complex 3b can be purchased on larger scale
from Umicore and on research quantities from Strem
(cat. no. 46-0298) .
(30) Nadelson, J (Sandoz, Inc.) US Patent 4,582,848
(31) Bae, J. ; Kim, J. (LG Chem, Ltd.) EP2332911A2.
(32) Kondo, T.; Kondo, A.; Tatani, K.; Kawamura, N.
(Kissei Pharmaceutical Co. Ltd.) US2012/122931 A1.
(42) a) Weigend, F. Phys. Chem. Chem. Phys. 2006, 8,
1057-1065; b) Weigend, F.; Ahlrichs, R. Phys. Chem.
Chem. Phys. 2005, 7, 3297-3305.
(33) a) Song, J. J.; Reeves, J. T.; Gallou, F.; Tan, Z.; Yee,
N. K.; Senanayake, C. H. Chem. Soc. Rev. 2007, 36,
1120–1132. b) Saab, F.; Bénéteau, V.; Schoentgen, F.;
Mérour, J.-Y.; Routier, S. Tetrahedron 2010, 66, 102–
110. c) (1) Mérour, J.-Y.; Routier, S.; Suzenet, F.; Jo-
seph, B. Tetrahedron 2013, 69, 4767–4834.
(43) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J.
Phys. Chem. B 2009, 113, 6378-6396.
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R''
Cl
R''
R'
[Pd(IPr*)(cinnamyl)Cl]
(Het)
R
0.5-2.0 mol%
(Het)
R'
R
N
N
Base
H
52-91% yield
Valuable heterocyclic compounds
Straightforward and practical assembly
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Easily accessible from
commercially available
starting materials
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