Palladium-Catalyzed Regioselective Alkynylation of Pyrroles and Azoles under Mild Conditions: Application to the Synthesis of a Dopamine D-4 Receptor Agonist

Article abstract of DOI:10.1021/acs.joc.5b01093

A mild and general method for the direct alkynylation of azoles such as pyrrole, indole, and 7-azaindole is described here. Using a simple catalytic system such as Pd(OAc)₂ (2.5 mol %), P(tBu)₂Me·HBF₄ (5 mol %), and NaOAc (2 equiv) allowed the regioselective introduction of various alkynyl residues at the C-2 position of pyrroles. Interestingly, C-2 alkynylation was also observed on C-3-substituted indoles, whereas classical C-3 alkynylation was obtained on selected unsubstituted indoles and 7-azaindole. Our methodology has been illustrated by the efficient synthesis of a potential schizophrenia drug (dopamine D-4 inhibitor).

Full text of DOI:10.1021/acs.joc.5b01093

Article
pubs.acs.org/joc
Palladium-Catalyzed Regioselective Alkynylation of Pyrroles and
Azoles under Mild Conditions: Application to the Synthesis of a
Dopamine D‑4 Receptor Agonist
Etienne Brachet*,†,‡ and Philippe Belmont*,†,‡
†Universite
FR-75006, France
‡Universite
́
Paris Descartes, Faculte
́
de Pharmacie de Paris, UMR CNRS 8638 (COMETE), 4 avenue de l’Observatoire, Paris
́
Sorbonne Paris Cite
́
(USPC), 12 rue de l’ecole de Medecine, Paris FR-75006, France
́
́
S
* Supporting Information
ABSTRACT: A mild and general method for the direct alkynylation of azoles such as pyrrole, indole, and 7-azaindole is
described here. Using a simple catalytic system such as Pd(OAc)2 (2.5 mol %), P(tBu)2Me·HBF4 (5 mol %), and NaOAc (2
equiv) allowed the regioselective introduction of various alkynyl residues at the C-2 position of pyrroles. Interestingly, C-2
alkynylation was also observed on C-3-substituted indoles, whereas classical C-3 alkynylation was obtained on selected
unsubstituted indoles and 7-azaindole. Our methodology has been illustrated by the efficient synthesis of a potential
schizophrenia drug (dopamine D-4 inhibitor).
in many bioactive compounds: for instance, compound 1
exhibits fungicidal activity,4 compound 2 is a hepatitis agent,5
and compound 3 targets the dopamine 4 receptor.6 With the
aim of building these compounds, many strategies have been
developed to ideally functionalize the pyrrole core. One of the
most recent and powerful breakthroughs in the direct
functionalization of azoles has been carried out by C−H
activation. This method has already been reported for the
introduction of many electrophiles, or pseudoelectrophiles,
onto heteroarene compounds.8
INTRODUCTION
■
Heterocycles are ubiquitous in nature and are constitutive of
many essential compounds.1 Nitrogen-contaning heterocycles
are probably the most popular and useful family of heterocycles
(e.g., pyrroles, indoles, purines),2 with various properties in
therapeutics, materials, and agrochemicals sciences.3 As shown
in Scheme 1, alkynylated pyrrole (or indole) patterns are found
Scheme 1. Bioactive Alkynylated Pyrrole-Containing
Compounds
As part of our efforts to find and develop new methods to
synthesize and functionalize heterocyclic structures,7 we
envisioned the functionalization of pyrroles, and particularly
the introduction of alkynyl residues at their C-2 position, in
order to obtain new building blocks. At first, we thought that
the most convergent strategy would be the direct introduction
of an alkynyl residue by an attractive C−H activation reaction.
However, although C−H arylation or C−H alkenylation has
been well described and reviewed in recent years for many
heteroarenes, including indoles or pyrroles,8 the C−H
alkynylation version has been much less explored, especially
for pyrroles.9 In fact, tremendous efforts in C−H alkynylation
Received: May 15, 2015
© XXXX American Chemical Society
A
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Scheme 2. State of the Art of C−H Alkynylation of Pyrroles
a
Table 1. Optimization Coupling Reaction of 1a with 2a under Various Conditions
b
c
entry
Pd (5 mol %)
PdCl2(PPh3)2
ligand (10 mol %)
base (2 equiv)
solvent (0.25 M)
conversn (%)
yield of 3a (%)
1
2
3
4
5
6
7
8
KOAc
toluene
toluene
toluene
toluene
toluene
toluene
dioxane
DMF
95
<5
15
Pd(OAc)2
PPh3
dppb
KOAc
Pd(OAc)2
KOAc
<5
Pd(OAc)2
Xphos
KOAc
<5
Pd(OAc)2
P(tBu)2Me·HBF4
P(tBu)2Me·HBF4 (5 mol %)
P(tBu)2Me·HBF4 (5 mol %)
P(tBu)2Me·HBF4
P(tBu)2Me·HBF4
P(tBu)2Me·HBF4
KOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
100
100
100
<5
71
85
85
Pd(OAc)2 (2.5 mol %)
Pd(OAc)2 (2.5 mol %)
Pd(OAc)2
d
9
Pd(OAc)2
toluene
toluene
100
100
24
78
e
10
Pd(OAc)2
a
Reaction conditions unless specified otherwise: 1a (0.50 mmol), 2a (0.25 mmol), Pd(OAc)2 (5 mol %), ligand (10 mol %), and base (0.50 mmol)
b
in solvent (1.0 mL) were heated in a sealed Schlenk tube at 50 °C for 10 h. Conversion was determined by 1H NMR on the crude reaction mixture.
c
d
e
Yield of isolated product. Reaction was run at 75 °C. The reaction was run at room temperature. Control experiments: no conversion at all was
observed in the absence of Pd(OAc)2 or L and in the absence of Pd(OAc)2 and L.
have been made by different research groups;10 however, when
we looked carefully for direct alkynylation of pyrroles in the
literature, we were surprised to find no general methods for
introducing a C(sp) moiety at the C-2 position of pyrroles,
despite its wide utility. To the best of our knowledge, only three
related examples of C−H alkynylation of pyrrole derivatives
have been reported, but with a limited scope for the nature of
pyrroles or alkynes used, which led us to examine this reaction
further. Indeed, in a seminal paper Gevorgyan and co-workers
were the first to report the efficient alkynylation of electron-rich
N-fused azoles10a (Scheme 2). In their case, one pyrrole α-
position was blocked, therefore avoiding potential dialkynyla-
tion reactions. Moreover, the use of unsubstituted pyrroles as
starting materials led only to poor yields of the alkynylated
products.11 Indeed, electron-rich structures were clearly needed
to carry out an efficient C−H alkynylation reaction.10a
Furthermore, in the case of a pyrrolo dimer with two free α-
positions (C-2 positions), Gevorgyan’s team had obtained the
C-2-disubstituted product, and the isolation of the mono-
substituted compound was not reported. Therefore, inspired by
Gevorgyan’s work and observing that very little information on
functionalized or unprotected pyrroles is known in the
literature, we decided to launch our investigations. Hence, it
may be important to find alternative and regioselective
reactions compatible with pyrroles exhibiting unsubtituted α-
positions. Indeed, another recent report based on C−H
alkynylation was published by Su and co-workers on several
heteroarenes (Scheme 2), but mostly concentrating on 2-
substituted thiophenes, by an oxidative strategy.12 In their
reaction only one example was reported with pyrrole and had a
low 40% yield due to concomitant dimerizations of both alkyne
and heterocycle moieties in a significant amount. Finally,
Waser’s group16 described the alkynylation of several
heteroarenes, especially pyrroles, using a hypervalent iodine
reagent under gold catalysis (Scheme 2). Despites the use of
mild conditions, only silylethynyl groups were introduced on
B
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a
Table 2. Scope of Bromoalkynes with N-Methylpyrrole
a
Reaction conditions: 1a (0.50 mmol), 2a (0.25 mmol), Pd(OAc)2 (2.5 mol %), P(tBu)2Me.HBF4 (5 mol %), and NaOAc (0.50 mmol) in toluene
(1.0 mL) were heated in a sealed Schlenk tube at 50 °C for 10 h.
pyrroles, and troubles with regioselectivity were observed on N-
substituted heterocycles.
palladium ligands on this reaction. Importantly, the results in
entries 2−5 (Table 1) demonstrated that the nature of the
ligand was crucial for the C−H alkynylation reaction. Indeed,
trialkylphosphines, especially Fu’s P(tBu)2Me.HBF4,14 proved
to be the best ligands for this reaction, giving the desired
product in a good 71% yield (Table 1, entry 5). Other type of
ligands such as mono- or bidentate species were less efficient in
this reaction and led to poor conversion of the starting
materials (Table 1, entries 2−4). Switching the base from
potassium acetate to sodium acetate (Table 1, entry 6) allowed
us to reach a better 85% yield. Other types of bases such as tert-
butylates, carbonates, and organic bases gave lower yields,
which is in accordance with a concerted mechanism
deprotonation route due to the acetate moiety.15 The catalytic
load could also be reduced from 5 to 2.5 mol % of Pd (Pd/L 1/
2) to afford a similar yield of 85% after 10 h (Table 1, entry 6).
Trying different solvents failed to improve the yields of the
reaction; interestingly, the reaction run in dioxane gave a yield
similar to that in toluene (Table 1, entries 6 and 7), and in
DMF no conversion was observed (Table 1, entry 8). The
amount of bromoalkyne and pyrrole derivatives was also crucial
to obtain good yields; indeed 2 equiv of N-methylpyrrole (1a)
for 1 equiv of 1-bromophenylacetylene (2a) gave the best yield
(85%). By diminishing the amount of N-methylpyrrole to 1.5
equiv, the yield of the C−H alkynylation reaction dropped to
74%, but still no dialkynylation product was observed; for this
reason we kept the ratio 2/1 between pyrroles and
bromoalkynes for our studies. We also investigated the effect
on temperature: increasing the temperature to 75 °C gave a
very low yield (24%, Table 1, entry 9), certainly due to the
Because of the reported regioselectivity and reactivity
limitations in obtaining C-2 alkynylated pyrroles, we were
motivated to develop an efficient method. Herein, we report a
mild and general method for a selective and efficient access to
C-2 regioselective alkynylation of pyrroles, using various
bromoalkynes as starting materials. The reactivity of related
heteroarenes will also be reported and discussed. An application
to the synthesis of a bioactive compound, a dopamine D-4
inhibitor, has also been investigated.
RESULTS AND DISCUSSION
■
To find the best reaction conditions, we chose in a model
reaction to use N-methylpyrrole 1a as the heteroarene moiety
and tested its reactivity toward 1-bromophenylacetylene (2a)
(Table 1). Bromoacetylene derivatives are readily available from
the corresponding terminal alkynes using AgNO3 as the catalyst
and N-bromosuccinimide as the brominating agent at room
temperature.13 Thus, we tried to find the best conditions to get
the desired alkynylated product at position 2 of pyrrole and to
avoid the formation of side products such as alkynylation in
position 39 or dialkynylation of positions C-2 and C-5. The
coupling was initially run following conditions reported
previously by Gevorgyan, PdCl2(PPh3)2 and KOAc in toluene,
setting our reactions at 50 °C.10a However, as expected we got
only a 15% yield of the desired product and traces of the C-3-
alkynylated product (Table 1, entry 1). Then, we started to
optimize the reaction conditions by changing first the palladium
source to Pd(OAc)2 (5 mol %) and to evaluate the impact of
C
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a
Table 3. Scope of Pyrrole-Containing Derivatives
a
Reaction conditions: 1b−p (0.50 mmol), 2 (0.25 mmol), Pd(OAc)2 (2.5 mol %), P(tBu)2Me·HBF4 (5 mol %), and NaOAc (0.50 mmol) in
toluene (1.0 mL) were heated in a sealed Schlenk tube at 50 °C for 10 h.
instability of the bromoalkyne derivatives, and when we
lowered the temperature to room temperature, we were
pleased to find that the reaction was still effective, giving rise
to the desired product in a good 78% yield; however, the
reaction took 4 days (Table 1, entry 10). These mild conditions
could be particularly interesting in total synthesis, for a late-
stage functionalization of a complex molecule. Not surprisin-
gly,10a chloro- and iodoalkynes were not efficient under these
reaction conditions, leading only to traces of products or
formation of diyne products (data not shown).
To conclude, we found our optimal conditions: 2.5 mol % of
Pd(OAc)2 with 5.0 mol % of P(tBu)2Me.HBF4 and NaOAc (2
equiv) in toluene at 50 °C over 10 h. With these conditions in
hand, we then explored the scope and limitations of this
process toward the different bromoalkynes 2a−l (Table 2) and
thereafter on the different heteroarene substrates 1b−o (Table
3).
First of all, bromoalkynes were obtained easily from a well-
described bromination reaction of the corresponding terminal
alkynes under AgNO3 catalysis using N-bromosuccinimide as
the brominating agent.13 Then, they were engaged in the C−H
alkynylation procedure with N-methylpyrrole (1a) (Table 2).
Gratifyingly, almost all of the bromoalkynes used in this study
were efficiently coupled under our optimized conditions.
Indeed, bromoalkynes possessing electron-withdrawing or
electron-donating groups in ortho, meta, or para positions
were efficiently introduced on the C-2 position of N-
methylpyrrole (1a). The model compound 3a was obtained
in a satisfactory 85% yield at the 0.25 mmol scale, and when we
increased the scale to 5 mmol, we still observed a good 75%
yield for this transformation. As described previously in the
optimization condition step, compound 3a was also obtained in
a good 78% yield at room temperature but after a longer
reaction time (4 days).
D
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Scheme 3. One-Pot Tandem Dialkynylation Reaction
Scheme 4. Synthesis of a Dopamine D-4 Agonist
Bromoalkynes substituted with electron-donating groups
were introduced efficienly to produce 3b−d in good yields
ranging from 68% to 77%. Phenylacetylene units possessing
fluoro (3e), nitro (3f), or ethyl ester substituents (3g) were
also successfully introduced (62−74% yield), especially the
sensitive ester function in an encouraging 67% yield.
Interestingly, it was also possible to introduce on N-
methylpyrrole (1a) an alkyl-substituted alkyne (octynyl
chain) in a good 81% yield (compound 3h). Furthermore, 1-
(bromoethynyl)cyclohex-1-ene, as an ene-yne substituent, was
introduced, giving rise to the product 3j in a reasonable 58%
yield, and silylethynyl-substituted pyrrole could also be formed
(compound 3k, 43%).
leading only to the degradation of the alkynyl bromide unit.
This result seems to indicate that electron-rich pyrroles are
necessary in order to perform the C−H alkynylation reaction
under our reaction conditions. Nevertheless, we were pleased
to observe that unprotected pyrroles, known to be very
sensitive17 and thus hard to engage in classical Sonogashira
reactions, were here good partners, giving the C-2-alkynylated
compound in a satisfiying 67% yield (4e). Differently alkyl
substituted pyrroles were also good partners in this reaction,
leading to compound 4g in 78% yield. Thanks to compound
4g, we were able to observe that when position 2 is blocked, the
alkynyl derivative can still be introduced, but now at position 3,
with a good 78% yield.
Moreover, 5-(bromoethynyl)-2-methoxypyridine was also a
good partner as a heteroarene substituent, yielding product 3i
(65% yield). However, when using simple 2-(bromoethynyl)-
pyridine we could not observe the formation of the desired
product 3l, and the reaction led only to the slow degradation of
the starting material.
We observed previously that electron-deficient substituents
were not well tolerated in this reaction (4f), and indeed the use
of 3-acetylpyrrole led to the alkynylated compound 4j with a
low 35% yield. An alkynyl- or aryl-substituted pyrrole
(compounds 4h,i) could also be engaged in this reaction,
giving the desired products in fair yields (61 and 55%,
respectively). Then we turned our attention on other
heterocycles. Thus, pyrroloisoindoline was a good partner,
giving the desired product 4k in an excellent 89% yield. Indoles,
N-protected by an aryl or alkyl substituent, were also good
partners for this reaction, giving compounds 4l−n regiose-
lectively alkynylated at their electron-rich C-3 position. 1-
(Bromoethynyl)-3-methoxybenzene was also reactive on the 7-
azaindole moiety, at the C-3 position, but with a low 37% yield
(4o). Moreover, as observed with compound 4d, other
heteroarenes (furane and thiophene) were strictly unreactive
under our reaction conditions (compound 4p), whatever the
nature of the bromoalkyne used.
Inspired by the synthesis of product 4h, we wondered if two
successive alkynylation reactions could be done in a one-pot,
two-step reaction using our protocol (Scheme 3). We thus
chose to work in the first step with equimolar quantities of
pyrrole 1a and 1-bromophenylacetylene, in order to avoid
competition in the second step between nonalkynylated N-
methylpyrrole (1a) with compound 3a toward 1-(bromoe-
thynyl)-4-methylbenzene. After checking the completion of the
first reaction (formation of compound 3a), we then added the
1-(bromoethynyl)-4-methylbenzene derivative and kept on
heating for 10 h more. We were pleased to isolate compound
After exploring the scope of the reaction with various alkynyl
derivatives on N-methylpyrrole (1a), we turned our attention
to the heteroarene counterparts (Table 3). Thus, we examined
not only differently substituted pyrroles but also other
heteroarenes. We were pleased to find that substituted pyrroles
were quite well tolerated under our reaction conditions. In fact,
the pyrrole N-position could be substituted by aryl, benzyl, or
heterobenzyl substituents (4a−d), giving the desired products
in satisfactory yields up to 79%. We observed that a bromine
atom on the C(sp) carbon is much more reactive than that on a
C(sp2) carbon, allowing access to product 4c in a satisfiying
59% yield. Compound 4c might be further functionnalized in
cross-coupling reactions to bring structural diversity. Interest-
ingly, the reaction conditions are very selective for the pyrrole
C-2 position, since the reaction of two different heteroarenes
linked together, in our case a pyrrole and a thiophene, led only
to the alkynylation at the pyrrole unit (4d, 64% yield). This is
particularly interesting, because thiophene is known to be
reactive in related C−H activation reactions.12,16 This
observation could be particularly useful in a late-stage
functionalization of a complex molecule possessing both
heteroarenes. However, the pyrrole N-substituted by an acyl
group (compound 4f) was unreactive under these conditions,
E
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4h in a good 69% yield on a one-pot, two-step procedure. To
the best of our knowledge, this is the first example of a
sequential C−H alkynylation reaction on pyrrole.
pathways (Scheme 6), with the prevalence of the electrophilic
alkynylation mechanism being justified by the regioselectivity
observed on the pyrrole ring (note that although the
mechanism is described here for pyrroles, the same mechanistic
pathway may occur with indoles, for which the more
nucleophilic center is in this case the C-3 position). Thus,
upon formation of the alkynylpalladium(II) intermediate A, the
nucleophilic attack of the pyrroles produces the iminium
intermediates B and B′. In the case of pyrroles unsubstituted at
their α-positions (or at the C-3 position for indoles),
deprotonation by the base would lead to rearomatization of
the pyrrole ring (C), leading after reductive elimination to the
C-2-alkynylated pyrrole. Alternatively, when pyrroles are
substituted at their α-positions (or at the C-3 position for
indoles), the iminium intermediate B′ may undergo a C-2/C-3
shift (C-3/C-2 shift for indoles),21 leading to the carbocation
C′, which upon rearomatization to the pyrrole ring (D′) and
reductive elimination produces the C-3-alkynylated pyrrole (or
the C-2-alkynylated indole).
Finally, we applied our methodology to the synthesis of the
dopamine D-4 agonist 3, of particular interest in the treatment
of schizophrenia (Scheme 4).6 Starting from the commercially
available 4-benzylpiperidone (4), we obtained the oxime
derivative, which was directly reduced by LiAlH4 to give the
4-aminobenzylpiperidine.6 Using a reported procedure,6 the
reaction of 4-aminobenzylpiperidine with 2,5-dimethoxytetra-
hydrofuran (5) gave pyrrole derivative 6,6 which successfully
underwent our C−H alkynylation protocol using
(bromoethynyl)benzene 2a to synthesize the desired dopamine
D-4 agonist 3, in a satisfiying 73% yield. The reported strategy6
required the selective pyrrole C-2 iodination of compound 6,
which was challenging. In our case bromination of the alkyne is
efficient and high-yielding; moreover, our alkynylation step is
totally regioselective for the pyrrole C-2 position.18
From a mechanistic point of view, the alkynylation reaction
seems to proceed most likely though an electrophilic
mechanism, as previously reported by Gevorgyan and co-
workers.10a Indeed, our methodology furnished exclusively 2-
alkynylpyrroles or 3-alkynylindoles, which support this kind of
mechanism.10a,c However, when both α-positions were blocked
(e.g., for the 2,5-dimethylpyrrole derivative), C-3-alkynylated
pyrrole 4g was obtained in a good 78% yield (Table 3 and
Scheme 5). In the same manner, when position 3 of indoles was
CONCLUSION
■
In summary, we have developed a C−H alkynylation method
on pyrroles and related azoles, allowing the introduction of a
variety of substituted alkynes. Combination of Pd(OAc)2 with
PMe(tBu)2·HBF4 as the catalytic system demonstrates a good
activity under mild conditions (50 °C) down to room
temperature; these conditions are still rare in palladium-
catalyzed C−H activation reactions. Reported methods in the
literature are known to proceed efficiently on furans,
thiophenes, and related heterocycles but are more reluctant
on pyrroles; therefore, our methodology is a gap-filling
alternative, since it offers a wide substitution pattern on pyrrole
and alkyne substrates, the only limitations occurring with
electron-deficient pyrroles. We proposed an electrophilic
alkynylation mechanism for this transformation, since pyrroles
and indoles react at their more nucleophilic position (C-2
pyrroles, C-3 indoles). Interestingly, when these positions are
masked, the reaction can still occur but on a different site (C-3
pyrroles, C-2 indoles). Moreover, this protocol has been
successfully applied to the synthesis of a bioactive ligand of the
dopamine D-4 receptor. Application of this method in
constructing new bioactive compounds is currently underway
in our laboratory and will be reported in due course.
Scheme 5. Further Reactivities on Methylated Azoles
EXPERIMENTAL SECTION
■
General Considerations. All glassware was oven-dried at 140 °C,
and all reactions were conducted under an argon atmosphere. For
chromatography, technical grade Et2O, cyclohexane, and ethyl acetate
solvents (EtOAc) were used. All new compounds were characterized
by 1H NMR, 13C NMR, and HR-MS analysis. 1H and 13C NMR
1
spectra were measured in CDCl3 at 300 or 400 MHz. H chemical
shifts are reported in ppm from the internal standard TMS or from
residual chloroform (7.27 ppm). The following abbreviations are used:
m (multiplet), s (singlet), br s (broad singlet), d (doublet), t (triplet),
dd (doublet of doublets), dt (doublet of triplets). 13C chemical shifts
are reported in ppm from the central peak of deuterochloroform
(77.14). Analytical TLC was performed on precoated silica gel 60 F-
254 plates. Silica gel 60 (230−400 mesh) was used for column
chromatography. The TLC plates were visualized either by UV light
(254 nm) or by a solution of phosphomolybdic acid in ethanol.
Melting points (mp) were recorded uncorrected. Low- and high-
resolution mass spectra (MS and HRMS) were analyzed by TOF-Q.
General Procedure for the Bromation of Terminal Alkynes. To a
solution of terminal alkyne (1.0 equiv, 30 mmol) in acetone (1 mL/1
substituted, we observed the alkynylation reaction at position 2
of compounds 7 and 8 (64% and 56% yields, respectively;
Scheme 5), which is in stark contrast in comparison to the
reported work.10c Indeed, Wang and co-workers did not
observe an alkynylation product on 3-substituted indole.
Furthermore, the formation following our method of the
known19 2-alkynylated indole 7 confirmed the regioselectivity
of the reaction.
On the basis of all these observations along with the
literature reports,10,20 we propose two competitive mechanistic
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Scheme 6. Proposed Mechanism
mmol) were successively added N-bromosuccinimide (1.1 equiv, 33
mmol) and AgNO3 (0.1 equiv, 3 mmol). The reaction mixture was
stirred in the dark for 3 h at room temperature. Upon completion the
reaction mixture was concentrated under reduced pressure, filtered
through a silica plug, and then eluted with cyclohexane. The solvent
was then concentrated, giving the desired product. The analytical data
obtained for bromoalkynes were similar to those reported in the
literature.13
equiv) was then added, and the reaction mixture was stirred for 10
h at 50 °C. Completion of the reaction was checked by TLC; the
resulting suspension was cooled to room temperature and filtered
through a pad of Celite with ethyl acetate as eluent, and the inorganic
salts were removed. The filtrate was concentrated, and purification of
the residue by silica gel column chromatography gave the desired
product.
1-Methyl-2-(phenylethynyl)-1H-pyrrole (3a).12 Following the
general procedure, a mixture of pyrrole (0.5 mmol, 41 mg) and
(bromoethynyl)benzene was heated at 50 °C for 10 h. The residue was
purified by flash chromatography over silica gel (cyclohexane/EtOAc
99/1) to afford the desired product 3a as a yellow oil: yield 85% (0.21
General Procedure for the C−H Alkynylation Reaction. A flame-
dried resealable tube was charged with Pd(OAc)2 (0.00625 mmol, 2.5
mol %), PMe(tBu)2·HBF4 (0.0125 mmol, 5 mol %), and NaOAc (0.5
mmol, 2 equiv). The tube was capped with a rubber septum,
evacuated, and back-filled with argon; this evacuation/back-fill
sequence was repeated one additional time. Toluene (1 mL per 0.25
mmol of bromoalkynes) was added through the septum. Liquid
reactants were then added: substituted pyrrole (0.5 mmol, 2 equiv)
and bromoalkynes (0.25 mmol, 1 equiv). The septum was replaced
with a Teflon screw cap. The Schlenk tube was sealed, and the mixture
was stirred at 50 °C (or room temperature in the case of product 3a).
Completion of the reaction was checked by TLC; the resulting
suspension was cooled to room temperature and filtered through a pad
of Celite with ethyl acetate as eluent, and the inorganic salts were
removed. The filtrate was concentrated, and purification of the residue
by silica gel column chromatography gave the desired product.
Procedure for the One-Pot Tandem Dialkynylation Reaction. A
flame-dried resealable tube was charged with Pd(OAc)2 (0.00625
mmol, 2.5 mol %), PMe(tBu)2·HBF4 (0.0125 mmol, 5 mol %), and
NaOAc (1 mmol, 4 equiv). The tube was capped with a rubber
septum, evacuated, and back-filled with argon; this evacuation/back-fill
sequence was repeated one additional time. Toluene (1 mL per 0.25
mmol of bromoalkynes) was added through the septum. Liquid
reactants were then added: pyrrole (0.25 mmol, 1 equiv) and
(bromoethynyl)benzene (0.25 mmol, 1 equiv). The septum was
replaced with a Teflon screw cap. The Schlenk tube was sealed, and
the mixture was stirred at 50 °C. Completion of the reaction was
checked by TLC; the resulting suspension was cooled to room
temperature. 1-(Bromoethynyl)-4-methylbenzene (0.25 mmol, 1
1
mmol, 39 mg); Rf = 0.66 (cyclohexane/EtOAc 95/5); H NMR (400
MHz, chloroform-d) δ 7.55−7.45 (m, 2H), 7.39−7.29 (m, 3H), 6.69
(br s, 1H), 6.50 (br s, 1H), 6.13 (br s, 1H), 3.75 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ 131.2 (2CH), 128.5 (2CH), 128.0, 123.9, 123.6,
115.8, 114.9, 108.3, 93.2, 81.4, 34.7; HR-MS (ESI+) m/z calculated for
C13H12N 182.0964, obtained 182.0959. These spectral data are in
agreement with the literature.12
1-Methyl-2-(p-tolylethynyl)-1H-pyrrole (3b). Following the
general procedure, a mixture of pyrrole (0.5 mmol, 41 mg) and 1-
(bromoethynyl)-4-methylbenzene was heated at 50 °C for 10 h. The
residue was purified by flash chromatography over silica gel
(cyclohexane/EtOAc: 97/3) to afford the desired product 3b as a
yellow oil: yield 77% (0.18 mmol, 40 mg); Rf = 0.30 (cyclohexane/
1
EtOAc 95/5); H NMR (300 MHz, chloroform-d) δ 7.34−7.28 (m,
1H), 7.13 (dd, J = 7.6, 1.3 Hz, 1H), 7.06 (dd, J = 2.5, 1.4 Hz, 1H),
6.95−6.86 (m, 1H), 6.78−6.67 (m, 1H), 6.53 (dd, J = 3.8, 1.7 Hz,
1H), 6.16 (dd, J = 3.8, 2.6 Hz, 1H), 3.86 (s, 3H), 3.78 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 159.5, 129.5, 124.6, 124.0, 123.8, 116.0,
115.7, 115.0, 114.6, 108.3, 93.1, 81.3, 55.4, 34.8; HR-MS (ESI+) m/z
calculated for C14H14N 196.1121 obtained 196.1118.
2-((3-Methoxyphenyl)ethynyl)-1-methyl-1H-pyrrole (3c).
Following the general procedure, a mixture of pyrrole (0.5 mmol, 41
mg) and 1-(bromoethynyl)-3-methoxybenzene was heated at 50 °C
for 10 h. The residue was purified by flash chromatography over silica
gel (cyclohexane/EtOAc 95/5) to afford the desired product 3c as a
G
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The Journal of Organic Chemistry
Article
yellow oil: yield 73% (0.18 mmol, 39 mg); Rf = 0.30 (cyclohexane/
EtOAc 95/5); H NMR (300 MHz, chloroform-d) δ 7.34−7.28 (m,
116.6, 113.4, 107.7, 93.9, 72.3, 34.5, 31.5, 29.0, 28.7, 22.7, 19.8, 14.2;
HR-MS (ESI+) m/z calculated for C13H20N 190.1590, obtained
190.1582.
1
1H), 7.13 (dd, J = 7.6, 1.3 Hz, 1H), 7.06 (dd, J = 2.5, 1.4 Hz, 1H),
6.95−6.86 (m, 1H), 6.78−6.67 (m, 1H), 6.53 (dd, J = 3.8, 1.7 Hz,
1H), 6.16 (dd, J = 3.8, 2.6 Hz, 1H), 3.86 (s, 3H), 3.78 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 159.5, 129.5, 124.6, 124.0, 123.8, 116.0,
115.7, 115.0, 114.6, 108.3, 93.1, 81.3, 55.4, 34.8; HR-MS (ESI+) m/z
calculated for C14H14NO 212.1070, obtained 212.1066.
2-Methoxy-5-((1-methyl-1H-pyrrol-2-yl)ethynyl)pyridine
(3i). Following the general procedure, a mixture of pyrrole (0.5 mmol,
41 mg) and 5-(bromoethynyl)-2-methoxypyridine was heated at 50 °C
for 10 h. The residue was purified by flash chromatography over silica
gel (cyclohexane/EtOAc 9/1) to afford the desired product 3i as a
yellow oil: yield 65% (0.17 mmol, 35 mg), Rf = 0.33 (cyclohexane/
EtOAc 9/1); viscous oil; 1H NMR (400 MHz, acetone-d6) δ 8.32 (t, J
= 1.9 Hz, 1H), 7.78 (dd, J = 8.6, 2.2 Hz, 1H), 6.99−6.58 (m, 2H),
6.48−6.21 (m, 1H), 6.05 (dd, J = 3.9, 2.3 Hz, 1H), 3.92 (s, 3H), 3.74
(s, 3H); 13C NMR (101 MHz, acetone) δ 164.2, 150.2, 141.7, 125.1,
116.0, 115.5, 114.3, 111.5, 108.8, 90.3, 83.5, 53.9, 34.7; HR-MS (ESI+)
m/z calculated for C13H13N2O 213.1022, obtained 213.1020.
2-(Cyclohex-1-en-1-ylethynyl)-1-methyl-1H-pyrrole (3j). Fol-
lowing the general procedure, a mixture of pyrrole (0.5 mmol, 41 mg)
and 1-(bromoethynyl)cyclohex-1-ene was heated at 50 °C for 10 h.
The residue was purified by flash chromatography over silica gel
(cyclohexane/EtOAc 9/1) to afford the desired product 3j as a yellow
oil: yield 58% (0.15 mmol, 28 mg); Rf = 0.53 (cyclohexane); viscous
1-Methyl-2-((3,4,5-trimethoxyphenyl)ethynyl)-1H-pyrrole
(3d). Following the general procedure, a mixture of pyrrole (0.5 mmol,
41 mg) and 5-(bromoethynyl)-1,2,3-trimethoxybenzene was heated at
50 °C for 10 h. The residue was purified by flash chromatography over
silica gel (cyclohexane/EtOAc 95/5) to afford the desired product 3d
as a yellow oil: yield 68% (0.18 mmol, 46 mg); Rf = 0.34
(cyclohexane/EtOAc 9/1); viscous oil; 1H NMR (400 MHz,
chloroform-d) δ 6.73 (s, 2H), 6.68 (br s, 1H), 6.48 (dd, J = 3.9, 1.8
Hz, 1H), 6.19−6.07 (m, 1H), 3.87 (s, 6H), 3.87 (s, 3H), 3.74 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 153.3 (2C), 138.8, 123.9, 118.6,
115.7, 115.0, 108.6 (2CH), 108.3, 93.1, 80.5, 61.1, 56.3 (2CH3), 34.8;
HR-MS (ESI+) m/z calculated for C16H17NNaO3 294.1106, obtained
294.1103.
1
oil; H NMR (400 MHz, chloroform-d) δ 6.62 (q, J = 1.9 Hz, 1H),
2-((2-Fluorophenyl)ethynyl)-1-methyl-1H-pyrrole (3e). Fol-
lowing the general procedure, a mixture of pyrrole (0.5 mmol, 41
mg) and 1-(bromoethynyl)-2-fluorobenzene was heated at 50 °C for
10 h. The residue was purified by flash chromatography over silica gel
(cyclohexane/EtOAc 95/5) to afford the desired product 3e as a
yellow oil: yield 62% (0.155 mmol, 31 mg); Rf = 0.31 (cyclohexane/
6.38−6.29 (m, 1H), 6.17−6.10 (m, 1H), 6.09−6.01 (m, 1H), 3.65 (s,
3H), 2.22 (s, 2H), 2.17−2.11 (m, 2H), 1.73−1.59 (m, 4H); 13C NMR
(101 MHz, CDCl3) δ 134.2, 123.3, 120.9, 116.3, 114.2, 108.1, 94.9,
78.6, 34.6, 29.4, 25.9, 22.5, 21.7; HR-MS (ESI+) m/z calculated for
C13H16N 186.1277, obtained 186.1273.
2-((Dimethyl(phenyl)silyl)ethynyl)-1-methyl-1H-pyrrole (3k).
Following the general procedure, a mixture of pyrrole (0.5 mmol, 41
mg) and (bromoethynyl)dimethyl(phenyl)silane was heated at 50 °C
for 10 h. The residue was purified by flash chromatography over silica
gel (cyclohexane/EtOAc 99/1) to afford the desired product 3k as a
yellow oil: yield 35% (0.10 mmol, 24 mg); Rf = 0.40 (cyclohexane/
EtOAc 95/5); viscous oil; 1H NMR (400 MHz, chloroform-d) δ
7.76−7.65 (m, 2H), 7.41 (dd, J = 4.6, 2.5 Hz, 3H), 6.65 (d, J = 2.4 Hz,
1H), 6.52−6.46 (m, 1H), 6.09 (d, J = 3.4 Hz, 1H), 3.70 (s, 3H), 0.51
(s, 6H); 13C NMR (101 MHz, CDCl3) δ 137.4, 133.9, 129.5, 128.1,
128.0, 124.0, 115.8, 108.1, 98.6, 96.4, 34.7, −0.6; HR-MS (ESI+) m/z
calculated for C15H18NSi 240.1203, obtained 240.1202.
1
EtOAc 98/2); viscous oil; H NMR (400 MHz, acetone-d6) δ 7.61−
7.50 (m, 1H), 7.41 (dtd, J = 9.8, 5.4, 2.7 Hz, 1H), 7.23 (td, J = 7.9, 1.6
Hz, 2H), 6.86 (d, J = 2.3 Hz, 1H), 6.46 (dd, J = 3.8, 1.8 Hz, 1H), 6.08
(dd, J = 3.9, 2.3 Hz, 1H), 3.76 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
164.0, 160.7, 132.8, 132.8, 129.6, 129.5, 124.3, 124.1, 124.1, 115.7,
115.5, 115.4, 115.3, 115.0, 112.4, 112.2, 108.4, 86.7, 77.4, 34.7; HR-MS
(ESI+) m/z calculated for C13H11FN 200.0870, obtained 200.0866.
1-Methyl-2-((3-nitrophenyl)ethynyl)-1H-pyrrole (3f). Follow-
ing the general procedure, a mixture of pyrrole (0.5 mmol, 41 mg) and
1-(bromoethynyl)-3-nitrobenzene was heated at 50 °C for 10 h. The
residue was purified by flash chromatography over silica gel
(cyclohexane/EtOAc 95/5) to afford the desired product 3f as a
yellow oil: yield 74% (0.19 mmol, 43 mg); Rf = 0.35 (cyclohexane/
EtOAc 95/5); viscous oil; 1H NMR (400 MHz, acetone-d6) δ 8.30 (t, J
= 1.9 Hz, 1H), 8.20 (ddd, J = 8.3, 2.3, 1.1 Hz, 1H), 7.92 (dt, J = 7.8,
1.3 Hz, 1H), 7.71 (t, J = 8.1 Hz, 1H), 6.89 (dd, J = 2.7, 1.7 Hz, 1H),
6.51 (dd, J = 3.8, 1.7 Hz, 1H), 6.09 (dd, J = 3.8, 2.6 Hz, 1H), 3.80 (s,
3H); 13C NMR (101 MHz, acetone) δ 149.3, 137.4, 135.5, 130.9,
126.0, 125.8, 123.3, 116.8, 115.2, 109.1, 91.8, 85.0, 34.8; HR-MS (ESI
+) m/z calculated for C13H11N2O2 227.0815, obtained 227.0814.
Ethyl 4-((1-Methyl-1H-pyrrol-2-yl)ethynyl)benzoate (3g).
Following the general procedure, a mixture of pyrrole (0.5 mmol, 41
mg) and ethyl 4-(bromoethynyl)benzoate was heated at 50 °C for 10
h. The residue was purified by flash chromatography over silica gel
(cyclohexane/EtOAc 9/1) to afford the desired product 3g as a yellow
oil: yield 67% (0.17 mmol, 43 mg); Rf = 0.35 (cyclohexane/EtOAc 9/
1-(4-Methoxyphenyl)-2-((3-methoxyphenyl)ethynyl)-1H-
pyrrole (4a). Following the general procedure, a mixture of 1-(4-
methoxyphenyl)-1H-pyrrole (0.5 mmol, 87 mg) and 1-(bromoethyn-
yl)-3-methoxybenzene was heated at 50 °C for 10 h. The residue was
purified by flash chromatography over silica gel (cyclohexane/EtOAc
97/3) to afford the desired product 4a as a yellow oil: yield 79% (0.20
1
mmol, 60 mg); Rf = 0.37 (cyclohexane/EtOAc 95/5); viscous oil; H
NMR (400 MHz, chloroform-d) δ 7.46 (d, J = 7.9 Hz, 2H), 7.18 (t, J =
7.7 Hz, 1H), 6.98 (d, J = 8.0 Hz, 2H), 6.92 (d, J = 7.2 Hz, 2H), 6.87−
6.74 (m, 2H), 6.70−6.59 (m, 1H), 6.27 (br s, 1H), 3.86 (s, 3H), 3.78
(s, 3H); 13C NMR (101 MHz, CDCl3) δ 159.4, 158.7, 133.2, 129.5,
126.2 (2CH), 124.6, 123.9, 123.5, 116.7, 115.8, 115.5, 114.4, 114.1
(2CH), 109.4, 92.97, 82.2, 55.7, 55.4; HR-MS (ESI+) m/z calculated
for C20H18NO2 304.1332, obtained 304.1327.
1-Benzyl-2-((3-methoxyphenyl)ethynyl)-1H-pyrrole (4b).
Following the general procedure, a mixture of 1-benzyl-1H-pyrrole
(0.5 mmol, 79 mg) and 1-(bromoethynyl)-3-methoxybenzene was
heated at 50 °C for 10 h. The residue was purified by flash
chromatography over silica gel (cyclohexane/EtOAc 95/5) to afford
the desired product 4b as a yellow oil: yield 72% (0.18 mmol, 52 mg);
Rf = 0.61 (cyclohexane/EtOAc 95/5); viscous oil; 1H NMR (400
MHz, chloroform-d) δ 7.39−7.31 (m, 2H), 7.30−7.27 (m, 1H), 7.24−
7.18 (m, 3H), 7.01 (dd, J = 7.7, 1.5 Hz, 1H), 6.94−6.90 (m, 1H), 6.85
(dd, J = 8.3, 2.6 Hz, 1H), 6.74 (dd, J = 2.9, 1.6 Hz, 1H), 6.54 (dt, J =
2.8, 1.4 Hz, 1H), 6.17 (t, J = 3.3 Hz, 1H), 5.24 (s, 2H), 3.80 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 159.4, 138.1, 129.5, 128.8, 127.7, 127.4,
1
1); viscous oil; H NMR (400 MHz, chloroform-d) δ 8.01 (d, J = 8.1
Hz, 2H), 7.52 (d, J = 8.1 Hz, 2H), 6.71 (s, 1H), 6.59−6.42 (m, 1H),
6.13 (d, J = 1.8 Hz, 1H), 4.38 (q, J = 7.0 Hz, 2H), 3.75 (s, 3H), 1.40 (t,
J = 7.1 Hz, 3H); 13C NMR (101 MHz, acetone) δ 166.2, 131.5 (2CH),
130.4, 130.3 (2CH), 129.0, 125.9, 116.5, 115.6, 109.1, 93.4, 85.6, 61.6,
34.8, 14.6; HR-MS (ESI+) m/z calculated for C32H31N2O4 (2M + H+)
507.2284, obtained 507.2288.
1-Methyl-2-(oct-1-yn-1-yl)-1H-pyrrole (3h). Following the
general procedure, a mixture of pyrrole (0.5 mmol, 41 mg) and 1-
bromooct-1-yne was heated at 50 °C for 10 h. The residue was purified
by flash chromatography over silica gel (cyclohexane/EtOAc 9/1) to
afford the desired product 3h as a yellow oil: yield 81% (0.20 mmol, 39
mg); Rf = 0.38 (cyclohexane); viscous oil; 1H NMR (300 MHz,
chloroform-d) δ 6.58 (t, J = 2.1 Hz, 1H), 6.30 (dd, J = 3.7, 1.6 Hz,
1H), 6.04 (t, J = 3.2 Hz, 1H), 3.64 (s, 3H), 2.43 (t, J = 7.0 Hz, 2H),
1.58 (d, J = 8.7 Hz, 3H), 1.44 (p, J = 6.7 Hz, 2H), 1.31 (q, J = 3.7 Hz,
3H), 0.90 (t, J = 6.5 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 122.7,
124.5, 123.8, 123.3, 115.9, 115.5, 115.4, 114.6, 108.9, 93.5, 81.4, 55.4,
51.6; HR-MS (ESI+) m/z calculated for C20H18NO 288.1383,
obtained 288.1376.
1-(2-Bromobenzyl)-2-((3-methoxyphenyl)ethynyl)-1H-pyr-
role (4c). Following the general procedure, a mixture of 1-(2-
H
DOI: 10.1021/acs.joc.5b01093
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bromobenzyl)-1H-pyrrole (0.5 mmol, 118 mg) and 1-(bromoethyn-
yl)-3-methoxybenzene was heated at 50 °C for 10 h. The residue was
purified by flash chromatography over silica gel (cyclohexane/EtOAc
99/1) to afford the desired product 4c as a yellow oil: yield 59% (0.15
purified by flash chromatography over silica gel (cyclohexane/EtOAc
99/1) to afford the desired product 4i as a yellow oil: yield 55% (0.14
mmol, 40 mg); Rf = 0.62 (cyclohexane/EtOAc 95/5); viscous oil; H
NMR (300 MHz, chloroform-d) δ 7.55−7.47 (m, 2H), 7.34 (dd, J =
8.4, 2.2 Hz, 5H), 6.97 (d, J = 8.8 Hz, 2H), 6.57 (d, J = 3.8 Hz, 1H),
6.16 (d, J = 3.8 Hz, 1H), 3.86 (s, 3H), 3.72 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 159.0, 136.5, 131.1, 130.1, 128.4, 127.9, 125.5, 123.6,
116.5, 114.7, 114.0, 108.4, 93.7, 82.0, 55.4, 33.1; HR-MS (ESI+) m/z
calculated for C20H18NO 288.1383, obtained 288.1377.
1
1
mmol, 43 mg); Rf = 0.50 (cyclohexane/EtOAc 95/5); viscous oil; H
NMR (400 MHz, acetone-d6) δ 7.65 (dd, J = 8.1, 1.7 Hz, 1H), 7.33 (t,
J = 7.6 Hz, 1H), 7.24 (ddd, J = 9.8, 4.9, 1.8 Hz, 2H), 7.02 (dt, J = 3.3,
1.6 Hz, 1H), 6.97−6.92 (m, 1H), 6.88 (d, J = 9.2 Hz, 2H), 6.71 (d, J =
7.7 Hz, 1H), 6.53 (dt, J = 3.5, 1.7 Hz, 1H), 6.21 (dd, J = 4.0, 2.3 Hz,
1H), 5.40 (s, 2H), 3.79 (s, 3H);13C NMR (101 MHz, acetone) δ
160.5, 138.7, 133.4, 130.5, 130.1, 129.2, 128.9, 125.2, 125.1, 123.9,
122.5, 116.3, 116.2, 116.1, 115.4, 109.6, 94.2, 81.8, 55.6, 52.0; HR-MS
(ESI+) m/z calculated for C20H17BrNO 366.0488, obtained 366.0471.
2-((3-Methoxyphenyl)ethynyl)-1-(thiophen-3-ylmethyl)-1H-
pyrrole (4d). Following the general procedure, a mixture of 1-
(thiophen-3-ylmethyl)-1H-pyrrole (0.5 mmol, 82 mg) and 1-
(bromoethynyl)-3-methoxybenzene was heated at 50 °C for 10 h.
The residue was purified by flash chromatography over silica gel
(cyclohexane/EtOAc 99/1) to afford the desired product 4d as a
yellow oil: yield 64% (0.16 mmol, 47 mg); Rf = 0.32 (cyclohexane/
EtOAc 98/2); viscous oil; 1H NMR (400 MHz, chloroform-d) δ
7.28−7.22 (m, 2H), 7.09 (dt, J = 7.6, 1.3 Hz, 1H), 7.04−7.00 (m, 2H),
6.95 (dd, J = 5.1, 3.5 Hz, 1H), 6.88 (ddd, J = 8.3, 2.7, 1.0 Hz, 1H), 6.78
(dd, J = 2.8, 1.6 Hz, 1H), 6.52 (dd, J = 3.8, 1.7 Hz, 1H), 6.16 (dd, J =
3.8, 2.7 Hz, 1H), 5.38 (s, 2H), 3.82 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 159.4, 140.2, 129.4, 126.9, 126.3, 125.6, 124.3, 123.7, 122.7,
116.0, 115.4, 115.0, 114.6, 109.0, 93.8, 81.0, 55.3, 46.1; HR-MS (ESI+)
m/z calculated for C18H16NOS 294.0947, obtained 294.0946.
1-(1-Methyl-5-(phenylethynyl)-1H-pyrrol-3-yl)ethan-1-one
(4j). Following the general procedure, a mixture of 1-(1-methyl-1H-
pyrrol-3-yl)ethan-1-one (0.5 mmol, 62 mg) and 1-(bromoethynyl)-
benzene was heated at 50 °C for 10 h. The residue was purified by
flash chromatography over silica gel (cyclohexane/EtOAc 98/2) to
afford the desired product 4j as a yellow oil: yield 35% (0.09 mmol, 21
mg); Rf = 0.34 (cyclohexane/EtOAc 7/3); viscous oil; 1H NMR (300
MHz, chloroform-d) δ 7.50 (dd, J = 6.5, 2.8 Hz, 2H), 7.36 (q, J = 2.8
Hz, 3H), 7.30 (d, J = 1.8 Hz, 1H), 6.87 (d, J = 1.8 Hz, 1H), 3.76 (s,
3H), 2.40 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 192.9, 131.3, 128.6,
128.5, 127.8, 125.3, 122.6, 117.6, 115.0, 93.9, 79.7, 35.2, 27.2; HR-MS
(ESI+) m/z calculated for C15H13NONa 246.0895, obtained 246.0899.
3-((3-Methoxyphenyl)ethynyl)-5H-pyrrolo[2,1-a]isoindole
(4k). Following the general procedure, a mixture of 5H-pyrrolo[2,1-
a]isoindole (0.5 mmol, 78 mg) and 1-(bromoethynyl)-3-methox-
ybenzene was heated at 50 °C for 10 h. The residue was purified by
flash chromatography over silica gel (cyclohexane) to afford the
desired product 4k as a yellow oil: yield 89% (0.23 mmol, 63 mg); Rf =
0.40 (cyclohexane); viscous oil; 1H NMR (300 MHz, chloroform-d) δ
7.52 (d, J = 7.6 Hz, 1H), 7.42 (d, J = 7.5 Hz, 1H), 7.35 (t, J = 7.5 Hz,
1H), 7.30−7.17 (m, 2H), 7.13 (dd, J = 7.6, 1.3 Hz, 1H), 7.05 (dd, J =
2.6, 1.4 Hz, 1H), 6.89 (ddd, J = 8.3, 2.6, 1.0 Hz, 1H), 6.65 (d, J = 3.7
Hz, 1H), 6.32 (d, J = 3.7 Hz, 1H), 5.01 (s, 2H), 3.84 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 159.5, 140.8, 139.8, 133.6, 129.6, 128.2,
125.6, 124.5, 123.9, 123.4, 119.3, 119.1, 116.0, 114.7, 111.5, 99.5, 93.7,
81.3, 55.5, 50.0; HR-MS (ESI+) m/z calculated for C20H16NO
286.1226, obtained 286.1215.
2-(Phenylethynyl)-1H-pyrrole (4e). Following the general
procedure, a mixture of 1H-pyrrole (0.5 mmol, 34 mg) and 1-
(bromoethynyl)benzene was heated at 50 °C for 10 h. The residue was
purified by flash chromatography over silica gel (cyclohexane/EtOAc
98/2) to afford the desired product 4e as a yellow oil: yield 67% (0.16
1
mmol, 28 mg); Rf = 0.32 (cyclohexane/EtOAc 95/5); viscous oil; H
NMR (400 MHz, chloroform-d) δ 8.79−8.16 (br s, 1H), 7.49 (dd, J =
7.1, 2.3 Hz, 2H), 7.33 (d, J = 6.6 Hz, 3H), 6.81 (d, J = 3.3 Hz, 1H),
6.56 (t, J = 2.9 Hz, 1H), 6.24 (d, J = 3.2 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 131.3, 128.5, 128.1, 123.3, 119.8, 115.0, 113.0, 109.6, 90.5,
82.0; HR-MS (ESI−) m/z calculated for C12H8N 166.0657, obtained
166.0655.
Ethyl 4-((1,2,5-Trimethyl-1H-pyrrol-3-yl)ethynyl)benzoate
(4g). Following the general procedure, a mixture of 1,2,5-trimethyl-
1H-pyrrole (0.5 mmol, 55 mg) and ethyl 4-(bromoethynyl)benzoate
was heated at 50 °C for 10 h. The residue was purified by flash
chromatography over silica gel (cyclohexane/EtOAc 98/2) to afford
the desired product 4g as a yellow oil: yield 78% (0.17 mmol, 28 mg);
Rf = 0.32 (cyclohexane/EtOAc 95/5); viscous oil; 1H NMR (400
MHz, chloroform-d) δ 8.56−8.19 (m, 1H), 7.49 (dd, J = 7.1, 2.3 Hz,
2H), 7.33 (d, J = 6.6 Hz, 3H), 6.81 (d, J = 3.3 Hz, 1H), 6.56 (t, J = 2.9
Hz, 1H), 6.24 (d, J = 3.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
131.3, 128.5, 128.1, 123.3, 119.8, 115.0, 113.0, 109.6 (2C), 90.5; HR-
MS (ESI+) m/z calculated for C18H19NNaO2 304.1313, obtained
304.1327.
1-Methyl-2-(phenylethynyl)-5-(p-tolylethynyl)-1H-pyrrole
(4h). Following the general procedure, a mixture of 1-methyl-2-
(phenylethynyl)-1H-pyrrole (0.5 mmol, 91 mg) and 1-
(bromoethynyl)benzene was heated at 50 °C for 10 h. The residue
was purified by flash chromatography over silica gel (cyclohexane) to
afford the desired product 4h as a yellow oil: yield 61% (0.15 mmol, 45
mg); Rf = 0.75 (cyclohexane/EtOAc 98/2); viscous oil; 1H NMR (400
MHz, chloroform-d) δ 7.51 (dd, J = 6.1, 2.1 Hz, 2H), 7.41 (dd, J = 8.1,
1.7 Hz, 2H), 7.35 (d, J = 6.6 Hz, 3H), 7.16 (d, J = 7.7 Hz, 2H), 6.46
(dd, J = 3.5, 1.6 Hz, 2H), 3.81 (s, 3H), 2.38 (s, 3H); 13C NMR (101
MHz, CDCl3) δ 138.6, 131.34, 131.29, 129.3, 128.5, 128.3, 123.2,
120.1, 117.8, 117.4, 114.7, 114.5, 94.0, 93.8, 81.3, 80.5, 32.9, 21.7; HR-
MS (ESI+) m/z calculated for C22H18N 296.1434, obtained 296.1424.
2-(4-Methoxyphenyl)-1-methyl-5-(phenylethynyl)-1H-pyr-
role (4i). Following the general procedure, a mixture of 2-(4-
methoxyphenyl)-1-methyl-1H-pyrrole (0.5 mmol, 62 mg) and 1-
(bromoethynyl)benzene was heated at 50 °C for 10 h. The residue was
1-Methyl-3-(p-tolylethynyl)-1H-indole (4l). Following the
general procedure, a mixture of 1-methyl-1H-indole (0.5 mmol, 62
mg) and 1-(bromoethynyl)-4-methylbenzene was heated at 50 °C for
10 h. The residue was purified by flash chromatography over silica gel
(cyclohexane) to afford the desired product 4l as a yellow oil: yield
1
74% (0.18 mmol, 45.5 mg); Rf = 0.20 (cyclohexane); viscous oil; H
NMR (400 MHz, chloroform-d) δ 7.82 (d, J = 7.9 Hz, 1H), 7.46 (d, J
= 8.1 Hz, 2H), 7.37−7.27 (m, 3H), 7.22 (ddd, J = 8.0, 6.8, 1.3 Hz,
1H), 7.16 (d, J = 7.9 Hz, 2H), 3.81 (s, 3H), 2.38 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ 137.6, 136.4, 132.1, 131.3, 129.3, 129.2, 122.8,
121.4, 120.4, 120.4, 109.7, 97.4, 91.2, 82.4, 33.2, 21.6; HR-MS (ESI+)
m/z calculated for C18H16N 246.1277, obtained 246.1277.
1-Methyl-3-(phenylethynyl)-1H-indole (4m). Following the
general procedure, a mixture of 1-methyl-1H-indole (0.5 mmol, 62
mg) and 1-(bromoethynyl)benzene was heated at 50 °C for 10 h. The
residue was purified by flash chromatography over silica gel
(cyclohexane) to afford the desired product 4m as a yellow oil:
yield 76% (0.185 mmol, 43 mg); Rf = 0.40 (cyclohexane); viscous oil;
1H NMR (400 MHz, chloroform-d) δ 7.82 (d, J = 7.9 Hz, 1H), 7.66−
7.45 (m, 2H), 7.44−7.04 (m, 7H), 3.82 (s, 3H). The analytical data
were identical with those reported.19
1-(4-Methoxyphenyl)-3-(p-tolylethynyl)-1H-indole (4n). Fol-
lowing the general procedure, a mixture of 1-(4-methoxyphenyl)-1H-
indole (0.5 mmol, 111 mg) and 1-(bromoethynyl)-4-methylbenzene
was heated at 50 °C for 10 h. The residue was purified by flash
chromatography over silica gel (cyclohexane) to afford the desired
product 4n as a yellow oil: yield 66% (0.17 mmol, 55 mg); Rf = 0.15
(cyclohexane); viscous oil; 1H NMR (300 MHz, chloroform-d) δ
7.91−7.83 (m, 1H), 7.54 (s, 1H), 7.48 (d, J = 8.1 Hz, 2H), 7.41 (d, J =
8.9 Hz, 2H), 7.27 (dd, J = 6.1, 3.2 Hz, 2H), 7.18 (d, J = 7.8 Hz, 2H),
7.05 (d, J = 8.9 Hz, 2H), 3.89 (s, 3H), 2.39 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 158.7, 137.8, 136.1, 132.1, 131.4, 131.4, 129.6, 129.2,
126.2, 123.4, 121.2, 121.1, 120.5, 115.0, 110.8, 99.3, 91.9, 82.0, 55.8,
I
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J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
21.7; HR-MS (ESI+) m/z calculated for C24H20NO 338.1544,
obtained 338.1539.
ACKNOWLEDGMENTS
■
This work was supported by a joint CNRS and INCa fellowship
(ATIP). E.B. is grateful to the Universite Paris Descartes and
Faculte de Pharmacie de Paris, for special research encourage-
3-((3-Methoxyphenyl)ethynyl)-1-methyl-1H-pyrrolo[2,3-b]-
pyridine (4o). Following the general procedure, a mixture of 1-
methyl-1H-pyrrolo[2,3-b]pyridine (0.5 mmol, 66 mg) and 1-
(bromoethynyl)-3-methoxybenzene was heated at 50 °C for 10 h.
The residue was purified by flash chromatography over silica gel
(cyclohexane) to afford the desired product 4o as a yellow oil: yield
37% (0.09 mmol, 25 mg); Rf = 0.50 (cyclohexane/EtOAc 98/2);
́
́
ment. The authors are grateful for mass spectrometry facilities
in Lyon, France (R. Simon, F. Albrieux, C. Duchamp, and N.
Henriques) and in Paris, France (A. Regazzetti and D.
Dargere). Special thanks, for helpful scientific discussions, are
1
viscous oil; H NMR (300 MHz, acetone-d6) δ 7.40 (dd, J = 9.1, 7.5
́ ́
extended to the team “Heterocycles et Peptides” UMR 8638.
Hz, 1H), 7.30−7.24 (m, 3H), 7.01 (ddd, J = 12.9, 7.8, 2.6 Hz, 2H),
6.90 (d, J = 7.7 Hz, 1H), 6.83 (dd, J = 2.7, 1.4 Hz, 1H), 3.84 (s, 3H),
3.79 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.5, 160.22, 140.5,
134.8, 130.8, 130.2, 124.4, 123.2, 122.5, 117.1, 116.5, 115.5, 104.4,
96.7, 87.0, 55.7, 32.6; HR-MS (ESI+) m/z calculated for C17H15N2O
263.1184, obtained 263.1180.
1-Benzyl-4-(2-(phenylethynyl)-1H-pyrrol-1-yl)piperidine (3).
Following the general procedure, a mixture of 1-benzyl-4-(1H-pyrrol-
1-yl)piperidine (0.5 mmol, 120 mg) and 1-(bromoethynyl)benzene
was heated at 50 °C for 10 h. The residue was purified by flash
chromatography over silica gel (cyclohexane/EtOAc 6/4) to afford the
desired product 3 as a yellow oil: yield 73% (0.18 mmol, 61 mg); Rf =
0.30 (cyclohexane/EtOAc 5/5); viscous oil; 1H NMR (300 MHz,
chloroform-d) δ 7.59−7.44 (m, 2H), 7.35 (m, 8H), 6.83 (t, J = 2.2 Hz,
1H), 6.50 (dd, J = 3.7, 1.6 Hz, 1H), 6.16 (t, J = 3.3 Hz, 1H), 4.29 (dq,
J = 15.9, 7.9, 7.3 Hz, 1H), 3.60 (s, 2H), 3.09 (d, J = 11.2 Hz, 3H),
2.29−2.15 (m, 2H), 2.09 (dd, J = 8.3, 3.0 Hz, 2H), 1.49 (dd, J = 14.7,
7.1 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 131.0, 129.3, 128.4, 127.9,
127.3, 123.6, 119.4, 115.0, 114.9, 114.5, 108.4, 93.6, 81.5, 62.9, 55.2,
53.1, 33.0; HR-MS (ESI+) m/z calculated for C24H25N2 341.2012,
obtained 341.2000.
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■
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1,3-Dimethyl-2-(phenylethynyl)-1H-indole (7). Following the
general procedure, a mixture of 1,3-dimethyl-1H-indole (0.5 mmol,
72.6 mg) and 1-(bromoethynyl)benzene was heated at 50 °C for 10 h.
The residue was purified by flash chromatography over silica gel
(cyclohexane) to afford the desired product 7 as a yellow oil: yield
1
64% (0.16 mmol, 39 mg); Rf = 0.70 (cyclohexane); viscous oil; H
NMR (300 MHz, chloroform-d) δ 7.64−7.52 (m, 3H), 7.45−7.32 (m,
3H), 7.32−7.22 (m, 2H), 7.13 (ddd, J = 8.0, 4.8, 3.2 Hz, 1H), 3.84 (s,
3H), 2.48 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 13C NMR (75
MHz, CDCl3) δ 137.3, 131.4, 128.5, 128.5, 127.5, 123.2, 123.2, 120.3,
119.4, 119.3, 117.1, 109.2, 97.8, 80.8, 30.7, 10.0. The analytical data
were identical with those reported.10g
̈
3-Methyl-2-(phenylethynyl)-1H-indole (8). Following the gen-
eral procedure, a mixture of 3-methyl-1H-indole (0.5 mmol, 72.6 mg)
and 1-(bromoethynyl)benzene was heated at 50 °C for 10 h. The
residue was purified by flash chromatography over silica gel
(cyclohexane/EtOAc 95/5) to afford the desired product 8 as a
yellow oil: yield 56% (0.14 mmol, 33 mg); Rf = 0.30 (cyclohexane);
1
viscous oil; H NMR (400 MHz, chloroform-d) δ 8.07 (br s, 1H),
7.64−7.54 (m, 3H), 7.40 (d, J = 6.0 Hz, 3H), 7.29 (dt, J = 13.7, 7.9 Hz,
2H), 7.17 (t, J = 7.4 Hz, 1H), 2.49 (s, 1H).13C NMR (75 MHz,
CDCl3) δ 136.0, 131.3, 128.4, 128.4, 128.0, 123.6, 122.9, 119.8, 119.2,
118.4, 116.6, 110.7, 95.1, 81.3, 9.6, HR-MS (ESI−) m/z calculated for
C17H12N 230.0970, obtained 230.0965.
ASSOCIATED CONTENT
* Supporting Information
■
S
Figures giving spectroscopic data of new compounds. The
Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.joc.5b01093.
(11) From the Gevorgyan paper:10a “...attempts with non-fused
heterocycles, such as pyrroles, under these reaction conditions,
afforded low yields of the corresponding alkynylation products”.
(12) Jie, X.; Shang, Y.; Hu, P.; Su, W. Angew. Chem., Int. Ed. 2013, 52,
3630.
(13) (a) Nie, X.; Wang, G. J. Org. Chem. 2006, 71, 4734. (b) Li, L.-S.;
Wu, Y.-L. Tetrahedron Lett. 2002, 43, 2427. (c) Zatolochnaya, O. V.;
Gevorgyan, V. Org. Lett. 2013, 15, 2562.
AUTHOR INFORMATION
Corresponding Authors
*E-mail for E.B.: etienne.brachet@parisdescartes.fr.
*E-mail for P.B.: philippe.belmont@parisdescartes.fr.
■
Notes
The authors declare no competing financial interest.
J
DOI: 10.1021/acs.joc.5b01093
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The Journal of Organic Chemistry
Article
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(18) In our case, 2 equiv of compound 6 is needed to reach a good
73% yield. However compound 6 could be recovered in the reaction
mixture, since about 90% of the remaining equivalent is recovered.
Decreasing the amount of compound 6 to 1.5 equiv led to a lower 61%
yield.
(19) Moulton, B. E.; Whitwood, A. C.; Duhme-Klair, A. K.; Lynam, J.
M.; Fairlamb, I. J. S. J. Org. Chem. 2011, 76, 5320.
(20) Tang, D.-T.; Collins, K. D.; Glorius, F. J. Am. Chem. Soc. 2013,
135, 7450.
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127, 8050.
K
DOI: 10.1021/acs.joc.5b01093
J. Org. Chem. XXXX, XXX, XXX−XXX