Metal-Free Activation of a C(sp)?H Bond of Aryl Acetylenes

Article abstract of DOI:10.1002/chem.201603003

C(sp)?H Bond activation of acetylene molecule still remains a challenge for synthetic organic chemists. In practice, acetylenes are activated by strong bases and metals. The first example for activating acetylenic protons under base and metal-free conditions is reported here. It involves a general method for synthesizing propargylic derivatives of cotarnine. An array of tetrahydroisoquinolines alkaloids was synthesized by C(sp)?H bond activation of aromatic acetylenes with cotarnine at room temperature. A DFT-based mechanism is proposed for the reaction.

Full text of DOI:10.1002/chem.201603003

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Accepted Article
Title: Metal-Free Activation of C(sp)-H Bond of Aromatic Acetylene
Authors: Laxmidhar Rout; Bibhuti Bhusan Parida; Jean-Claude Florent; Ludger Joh-
hanne; Santosh Kumar Choudhury; Ganngam Phaomei; Scalnon Joe; Emma-
nuel Bertounesque
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To be cited as: Chem. Eur. J. 10.1002/chem.201603003
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Metal-Free Activation of C(sp)-H Bond of Aromatic Acetylene
Laxmidhar Rout,[a], [b]* Bibhuti Bhusan Parida,[b]* Jean-Claude Florent,[b] Ludger Johannes,[b] Santosh
Kumar Choudhury[a], Ganngam Phaomei,[a] Joe Scanlon,[c] and Emmanuel Bertounesque,[b]*
Dedication ((optional))
Abstract: C(sp)-H bond activation of acetylene molecule still
remains a challenge for synthetic organic chemist. In practice, It is
activated by strong base and metal atoms. A very first example for
activating acetylenic proton under base and metal-free conditions
has been reported here. It gives a general method for synthesizing
propargylic derivatives of cotarnine. An array of tetrahydro-
isoquinolines alkaloids was synthesized by C(sp)-H bond activation
of aromatic acetylenes with cotarnine at room temperature. A DFT
based mechanism is proposed for following reaction has been
revealed.
Among them, C(sp)-H activation is more challenging in
comparison with C(sp3)-H, C(sp2)-H.[1] In the continuation of
our study[7] for carbon-carbon bond formation, we are
interested for insertion of acetylene functionality in
cotarnine at 5-position (Scheme 2). In particularly, 9th and
5th position[8] of cotarnine is equally important for displaying
important pharmacological property such as anti-tussive,
anti-cancer (Scheme 1). Hence, Functionalization and
derivatisation of 5-position is little explored and needs
immediate attention in order to synthesize the diverse
example of noscapine analogues. In a single example,
silver salt[9] of acetylene is used as nucleophile for C-C
bond formation of cotarnine with phenyl acetylene.
The C-H bond in acetylene is one of the strongest bond
with a bond-energy of 140 kcal/mol (De) in comparison to
the C-H bond in methane (bond-energy of 112 kcal/mol)
and the C-H bond in ethylene (118 kcal/mol).[1] Hence,
cleavage of C-H bond in acetylene still remains an
important challenge behind synthetic chemist. In most
cases, acetylene C(sp)-H bond is activated by either use of
strong base (BuLi / NaNH2/KOH)[2] or use of noble metals
such as Pd(Sonogasira),[3] Cu(Sharpless click chemistry), [4]
other metals[5] On other hand, activation of acetylenic
C(sp)-H bond under metal–, and base–free conditions is
not so far reported in the literature. Here in, we wish to
report the activation of acetylenic C(sp)-H bond without use
of any metal and base under room temperature.
Scheme 1. Diversification strategy adopted for cotarnine to synthesize
noscapine analouges
Results and discussion
During our study, we noticed that, the acetylenic group
could be installed at 5th position of cotarnine by replacing
hydroxy group, when phenyl acetylene 2a reacts with
cotarnine
1 in 1:1 ratio (Table 1). This is the first and new
example in literature where we were able to install
acetylene group under base and metal-free conditions. The
reaction afforded C-C coupled product in 82% yield after 72
h under room temperature using methanol as solvent
(Table 1). This result suggested that NEt3 has no role and at
all not required for above reaction (Table1, entry 1). Further
heating the reaction in methanol up to 55o C did not afford
any good yield. Aprotic polar solvents such as CH2Cl2 and
CH3CN were found ineffective (entries 5 and 6) for this
reaction compared with protic polar solvents. Methanol and
ethanol were found equally good (entry 2 vs entry 4) while
water afforded a comparable yield (62%) with a longer
reaction time (entry 8). Aqueous methanol afforded also a
comparable yield (entry 10) but the solubility issue of
acetophenone became problematic when increasing the
percentage of water (entries 8). So methanol/ethanol are
the solvents of choice for a variety of synthesis.
Figure 1. Dissociation energy for C-H bond activation
Carbon-Carbon bond formation via C-H activation is an
important strategy for synthesis of important synthetic
intermediates and natural products that are of biological
interest.[6]
[a] Prof. Laxmidhar Rout, Dr. G. Phaomei, S. Choudhury
Department of Chemistry, Berhampur University
Bhanjabihar, Odish-760007, India
E-mail: routlaxmi@gmail.com, ldr.chem@buodisha.edu.in
[b]
Dr. B. B. Parida, Dr. J.-C. Florent, Dr.
Bertounesque,
L. Johannes, Dr. E.
Chemical Biology of Membranes and Therapeutic Delivery, Institut Curie,
Research Center, U1143 INSERM, UMR 3666 CNRS, 26 rue d’Ulm,
75248 Paris, Cedex 05, France.
[c] Prof. J. Scanlon
Department of Chemistry, Rippon College USA
Supporting information for this article is given via a link at the end of the
document.((Please delete this text if not appropriate))

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corresponding C(sp)-H cleavage product 3c-3d in 80-81%
yield, where as bulkier group 4-t-Butyl 2e in p-position gave
75% product 3e (Scheme 2). Phenyl acetylenes with
electro donating groups such as 4-OMe-, and 4-OEt- in
para position afforded low yield (69-70%).
Table 1. Standardization table for reaction of cotarnine 1 and phenyl
acetylene 2a
Entry[a]
Solvent
Temp.
Yield(%) 3a[b]
1[c]
2
MeOH
MeOH
MeOH
EtOH
25 °C
25 °C
82
82
80
78
0
3
55 °C
Scheme 3. Selectivity of reaction of 1-(4-ethynylphenyl) ethanone cotarnine
2n with cotarnine 1a.
4
25/ 55 °C
25 / 55 °C
25 °/40°C
25 °C/ 55 °C
25 °C
5
CHCl3
CH2Cl2
CH3CN
H2O
6
0
Phenyl acetylenes containing halogen group in the ring
such as 2-chloro-, and 4-bromo-, afforded similar yileds (78-
79%). Surprisingly, presence of electron withdrawing group
such as 2,5-trifluoromethane 2l afforded a click solid
product immediately after stirring the reaction for 2-3 h in
methanol. The product 3i is just isolated by simple filtration
in >90% yield.
7
8[e]
5
62
60
74
9
THF
25 °C
10
50% MeOH
25 °C
[a] 1 (2 mmol) and 2 (2 mmol) were dissolved in 1 ml of solvent for 72 h. [b]
Isolated yields. [c] NEt3. [d] No base was used. * 3a collected by simple
filtration. [e] 96 h.
The main core unit cotarnine
1 could be synthesized in gram
scale by oxidative degradation of commercially available
(S,R)-noscapine with 14% HNO3 (See Supp. inf.).[10]
Scheme 4. Reactivity of aromatic acetylenes with 9-bromo cotarnine 1b
It is noteworthy that, in case of (2-ethynylphenyl)
methanol 2k, highly chemoselective C-C cross coupling is
preferred over products resulting from the reactivity of
hydroxy group. The corresponding product 3k is isolated in
>80% yield after 72h. Similarly, the substrate containing
cyanide group in the phenyl acetylene group 2m afforded
corresponding C-C product 3m in 77% product along with
hydrolyzed product (5-10%) of methanol.
Scheme 2. Reactivity of aromatic acetylenes with cotarnine 1
With optimized conditions in our hand, we studied the
scope of this reaction with a broad range of acetylenes
(Scheme 3-4). First, we studied the reaction scope of
aromatic
acetylenes
2a-2m
with
cotarnine
1.
Reaction of phenyl acetylene containing acetyl group1-(4-
ethynylphenyl) ethanone 2n in 1:1 with 2a afforded both
product 3n and 3n in 1:1.8 ration in 82% yield, where as
1:2 ratio of reactant afforded only 3n in 75% yield (Scheme
3).[7]
Phenylacetylenes containing alkyl group such as 2-
methylphenyl acetylene afforded 78% isolated after 72 h
under similar conditions. Similarly, alkyl groups in para-
position such as 4-methyl, (2b) and 4-ethyl-(2c) afforded

Chemistry - A European Journal
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COMMUNICATION
formation of product with aliphatic acetylenes indicates that
an aromatic conjugation with alkyne moiety favours this
reaction.
Table 2. Calculated Gibbs energies including solvation for each step of the
reaction of cotarnine with phenylacetylene in kcal/mol.
Scheme 5. Reactivity of aliphatic acetylenes with 9-bromo cotarnine 1b
Components[a]
G(solv)
0.0
Cotarnine + 2 phenylacetylene
Intermediate I + 2 phenylacetylene
Intermediate II + phenylacetylene
0.1
In parallel to cotarnine
sup. Info. for Synthesis)[8] also been further investigated
with phenyl acetylene 2a, 2o-t Under similar conditions,
1, 9-bromo cotarnine 1b (See
8.5
Intermediate III + phenylacetylene anion
Intermediate IV + H2O + phenylacetylene anion
Intermediate V + H2O + phenylacetylene anion
Product + phenylacetylene + H2O
35.1
32.4
24.8
-10.8
.
phenyl acetylene afforded C-C coupled product 3o in 78%
yield. Similarly, 4-t-Butyl, 4-bromo, 4-fluoro, 3-chloro-
[a] All structures were optimized using the M06L density functional with the 6-
311+G(2df,p) basis set using density fitting. All stationary points were
confirmed by vibrational frequency calculations. Solvation effects were
included by single point calculations of gas-phase geometries with the SMD
implicit solvation model for methanol (See Supp. Info).
afforded (64-75%) low yield in comparisons to cotarnine 1.
The presence of electron withdrawing group such as 2,5-
trifluoromethane 2i afforded a click product during the
reaction. The product 3t is just isolated by simple filtration in
>80% yield (Scheme 4). Surprisingly, aliphatic acetyls such
as cyclopropyl-, cyclohexyl, and trimethyl silyl acetylene
afforded no product under similar conditions (Scheme 5).
The dehydration of cotarnine from a proton donated from
phenylacetylene results in an intermediate I-a that is 5.8
kcal/mol higher in energy than the starting reactants. For
cyclopropylacetylene, this increases to 9 kcal/mol. This
could show agreement with the experimentally observed
results of phenylacetylene resulting in product, but
cyclopropyl acetylene leading to no reaction. However,
Proposed Mechanism:
In order to determine the scope and mechanism, 2-methyl-
1,2,3,4-tetrahydroisoquinolin-1-ol 5 was synthesized in 80% by
basic hydrolysis of its salt 2-methyl-3,4-dihydroisoquinolin-2-ium
iodide 4 (See sup info).[11,7,15] The reaction of cotarnine
backbone 5 with phenylacetylene 2a afforded coupling product
4a in 80% yield, indicating that the presence of electron-
donating groups on the aromatic ring of the cotarnine derivative
is not crucial for the reaction to proceed (Scheme 6).
Nucleophillic product 5a is not formed by reaction of 1 with 2a in
CD3OD even at -30°C in presence of benzophenone 5. To avoid
any trace of KOH in the cotarnine during its synthesis,[7,14] 1 was
washed many times with water to avoid trace of formation of
potassium acetylide.[2d-f]
when cotarnine is replaced by a truncated structure
5
without donating groups, the relative energy for the
intermediate increases to 12.0 kcal/mol. Experimentally,
this was found to react with phenylacetylene.
Scheme 7. Proposed mechanism for reaction of cotarnine and phenylacetylene.
In conclusions, Here in, we have revealed very first
examples for the activation of acetylenic proton without use
of base and metals atoms. It gives a general method for
Scheme 6. A) Synthesis of 2-methyl-3,4-dihydroisoquinoline 5, B) NMR
experiment to trap the anion intermediate 5a.
synthesizing
propargylic
derivatives
of
cotarnine.
Mechanism is proposed by both experimental and DFT
based calculation. The method is useful for synthesis of
isoquinoline alkaloids under mild conditions. The application
of the process is underway in laboratory.
The DFT calculation study reveals that the ring-
opened aldehyde[12]
cotarnine
I
is shown to be nearly isoenergetic as
1
(Scheme 7). Intermediate II, resulting from the
addition of phenylacetylene, is over 8 kcal/mol higher in
energy (Table 2). The proposed intermediate III could not
be located; however, a stable minima was found where the
Experimental Section
amine group was protonated. Intermediates III
,
IV, and
V
Synthesis of 3a: To an oven-dried, 5 mL round bottom flask equipped
was charged with cotarnine 1 (237 mg, 1 mmol) and phenyl acetylene 2a
(102 mg, 1 mmol) in methanol (1 mL), and the resulting mixture was
were found to be too high in energy (~32 and ~25 kcal/mol)
for this mechanism to be considered feasible. The non-

Chemistry - A European Journal
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COMMUNICATION
stirred at room temperature for 72h. The reaction mixture was subjected
to chromatography with short pad of silica gel using hexane and ethyl
acetate as eluent. The product was collected to afford 3a (264 mg, 82%)
as colorless liquid.
Colorless Liquid, 1H NMR (300 MHz, CDCl3): δ 2.59 (s, 3H), 2.67-2.62 (m,
1H), 2.80-2.67 (m, 1H), 3.29-3.02 (m, 2H), 4.04 (s, 3H), 4.94 (s, 1H),
5.88 (s, 2H), 6.34 (s, 1H), 7.25-7.20 (m, 2H), 7.40-7.39 (m, 2H); 13C
NMR (75 MHz, CDCl3): δ 28.77, 43.11, 46.78, 51.22, 59.66, 85.76, 85.73,
100.80, 103.01, 121.09, 123.40, 127.43, 127.88, 128.16, 131.73, 134.60,
139.96, 148.39 ; HRMS (ESI) Calcd for C20H19NO3; (MH+): 322.1443;
Found: 322.1437.
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Acknowledgements
This work has been supported by Institut Curie, CNRS,
INSERM, La Fondation Pierre-Gilles de Gennes, La Fondation
pour le développement de la chimie des substances naturelles
et ses applications, Institut de Chimie (CNRS), UGC-Start-up
Grant, India. Innovation-cum-Incubation Centre, Planning and
Coordination Department, Govt. of. Odisha, India
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Keywords: Phenylacetylene • cotarnine • alkaloid • isoquinoline•
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Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
10.1002/chem.201603003
Laxmidhar Rout,[a], [b]* Bibhuti Bhusan
Parida,[b]* Jean-Claude Florent,[b] Ludger
Johannes,[b] Santosh Kumar Choudhury[a],
Ganngam Phaomei,[a] Joe Scanlon,[c] and
Emmanuel Bertounesque[b]*
Text for Table of Contents
Page No. – Page No.
C(sp)-H bond activation of acetylene molecule still remains a
challenge for synthetic organic chemist. In practice, It is activated by
strong base and metal atoms. A very first example for activating
acetylenic proton under base and metal-free conditions has been
reported here. It gives a general method for synthesizing propargylic
derivatives of cotarnine. An array of tetrahydroisoquinolines
alkaloids was synthesized by C-C bond formation between cotarnine
and aromatic acetylenes at room temperature. A DFT based
mechanism is proposed for following reaction.
Title: Metal-Free Activation of C(sp)-H
Bond of Aromatic Acetylene