Regioselective Pd-Catalyzed Carbopalladation/Decarboxylative Allylic Alkynylation of ortho-Iodoallenamides with Alkynyl Carboxylic Acids

Article abstract of DOI:10.1021/acs.joc.9b01408

A regioselective Pd-catalyzed domino carbopalladation/decarboxylative allylic alkynylation of ortho-iodoallenamides with alkynyl carboxylic acids was studied. This domino process, based on the consecutive formation of C(sp²)-C(sp²) and C(sp³)-C(sp) bonds, was originally achieved for the design of a novel library of prop-2-ynyl isoquinolinones and then extended to indoles. Finally, a general three-step one-pot strategy involving in situ generation of allenamide, π-allyl-Pd complex formation, and decarboxylative allylic alkynylation was subsequently set up.

Full text of DOI:10.1021/acs.joc.9b01408

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Note
Regioselective Pd-Catalyzed Carbopalladation / Decarboxylative Allylic
Alkynylation of ortho-Iodoallenamides with alkynyl carboxylic acids
JONATHAN HEDOUIN, Vincent Carpentier, Romain M. Q. Renard,
Cédric Schneider, Isabelle Gillaizeau, and Christophe Hoarau
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01408 • Publication Date (Web): 18 Jul 2019
Downloaded from pubs.acs.org on July 19, 2019
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Regioselective Pd-Catalyzed Carbopalladation / Decarboxylative
Allylic Alkynylation of ortho-Iodoallenamides with alkynyl
carboxylic acids
Jonathan Hédouin,[a] Vincent Carpentier,[a] Romain M. Q. Renard,[a] Cédric Schneider,[a]*
Isabelle Gillaizeau,[b]* Christophe Hoarau[a]*
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[a] Normandie Univ, UNIROUEN, INSA Rouen, CNRS, COBRA (UMR 6014), 76000 Rouen, France
Institute of Organic and Analytical Chemistry, ICOA UMR 7311 CNRS, Université d’Orléans, rue de
Chartres, 45100 Orléans, France
[b]
christophe.hoarau@insa-rouen.fr
cedric.schneider@univ-rouen.fr
isabelle.gillaizeau@univ-orleans.fr
 Carbopalladation / decarboxylative allylic alkynylation

I
R2
N
Y
Z
R2
Y = (CH2)n, CO
Z = Boc, CH3
HO2C
[Pd0]
N
Y
Z
Broad substrate scope
Good functional group tolerance
I
N
Me

One-pot isomerization / carbopalladation /
decarboxylative allylic alkynylation
O
Abstract: A regioselective Pd-catalyzed domino carbopalladation / decarboxylative allylic
alkynylation of ortho iodoallenamides with alkynyl carboxylic acids was studied. This domino
process, based on the consecutive formation of C(sp2)-C(sp2) and C(sp3)-C(sp) bonds, was
originally achieved for the design of novel library of prop-2-ynyl isoquinolinones and then
extended to indoles. Finally, a general three-step one-pot strategy involving in situ
generation of allenamide, π-allyl-Pd complex formation and decarboxylative allylic
alkynylation was subsequently set up.
The rapid construction of valuable heterocycles from readily accessible starting material is
inarguably topic of key importance in modern organic synthesis. In recent years, transition-
metal-catalyzed domino reactions have received significant attention due to their
convenience in assembling multiple bonds in a one-pot sequence, thus providing an efficient
and step-economical route for the synthesis of complex heterocycles.1 A representative
strategy in the domino construction of standard important classes of five- and six-membered
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heterocycles containing nitrogen is the generation of π-allyl-Pd(II) intermediates from the
intra- or intermolecular carbopalladation of halogenated (hetero)aromatics onto standard
allenamide, which can be further captured by organometallics, nucleophiles or oxidants in a
cascade sequence (Scheme 1, eq 1).2,3 To expand the functional diversity in the termination
step, it is of great synthetic interest to introduce high value-added functions, as they offer
several options for chemical-modulation and/or reactivity. Among them, alkynes are
important motifs found in a wide range of natural products, pharmaceutical agents, and
materials, that display valuable utility as building blocks in organic chemistry.4 While a
remarkable advance has been made in the Pd-catalyzed domino reaction by interception of
the σ-alkyl-Pd(II) intermediate with terminal alkyne5 or arylpropiolic acids,6 no example has
been reported so far for the trapping of the η3-allylpalladium intermediate in order to
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construct heterocycles bearing alkyne functionalities.
R
Eq 1 Domino reaction with allenamides


N
Y
Z
Ar-M, Nu (N,O..)
PdX

X
[Pd0]
N
N
R2
Y
Z
Y
Z
Y = (CH2)n, CO
Z = alkyl, Boc, Tos, Ac
HO2C
R2
Eq 2, This work:

Pd-catalyzed
carbopalladation / decarboxylative allylic
alkynylation of allenamide with propiolic acid
N
Y
Z
Broad substrate scope
Good functional group tolerance
NH
N
H
O
Scheme 1. Broadening of the functional diversity in Pd-catalyzed domino construction /
functionalization of heterocycles
The Pd-catalyzed allylation of carbon nucleophiles via π-allylpalladium complexes, the
Tsuji-Trost reaction, is one of the most important developments in modern synthetic
chemistry.7 Notably, the Pd-catalyzed allylic alkynylation with pre-functionalized allylic
compounds by coupling terminal alkynes8 or propiolic acid derivatives9 has received
attention because it provides a convenient and direct approach to construct the 1,4-enyne
moiety.10 In this context, we envisioned that allenamides11 could serve as allylic electrophile
precursors via the in situ generation of a transient η3-allylpalladium intermediate resulting
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from the intramolecular carbopalladation step. In view of our interest in the development of
new decarboxylative cross-coupling methodologies12 and new Pd-catalyzed domino
reactions,13 we designed an original Pd-catalyzed sequence of carbopalladation of ortho-
iodoallenamides completed by intermolecular decarboxylative allylic alkynylation using
available alkynyl carboxylic acids14,15 (Scheme 1, eq. 2). They are known to be good
alkynylating agents in Pd-catalyzed decarboxylative cross-coupling without the need of
bimetallic catalytic systems or other activators usually required to conduct Sonogashira-type
cross-coupling. Therefore, this methodology offers an original step-economical and
regiocontrolled synthetic pathway for the construction of isoquinolones and indoles bearing
alkyne functionalities with a transient η3-allylpalladium intermediate. Notably, the scope of
terminal alkynes can be expanded to aryl, heteroaryl and alkyl substituents.
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Our initial investigations focused on the Pd-catalyzed domino intramolecular
carbopalladation / decarboxylative allylic alkynylation of phenylpropiolic acid (1A) with the
ortho-iodoallenamide 2a as model substrate. The results are summarized in Table 1. In the
presence of Pd(OAc)2 (10 mol%), and PCy3•HBF4 (20 mol%) as ligand in 1,4-dioxane, we were
able to isolate the desired isoquinolone 3aA in 70% yield. No improvement in the yield was
observed when the reaction was carried out using different solvents (Entries 2-3).16 We then
evaluated the reaction parameters. After screening various palladium sources, Pd(OAc)2
proved to be the best catalyst.16 Moreover, Pd(OAc)2 in conjunction with other alkyl
phosphine ligands or bidentate phosphines showed no improvement (Entries 4-6).16 The
influence of bases was next evaluated and it was found that the nature of the base as well as
its counter-ion were crucial parameters for the decarboxylative step, since the phenyl
acetylene resulting from the protodecarboxylation side-reaction was obtained mostly when
other carbonates or amine bases were used instead of Cs2CO3 (Entries 7-9).16 The beneficial
use of PivOH as additive, which has been previously shown to stabilize the π–allyl Pd(II)
complex in transition metal-catalyzed direct allylation,17 gave the alkynylated isoquinolone
3aA in 73% yield (Entry 10).
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Table 1. Optimal screening conditions.a
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Pd(OAc)2 (10 mol%)
Ligand (20 mol%)
Additive (0-30 mol%)
Base (3 equiv)

I
Solvent, 110 °C, 3 h
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+
N
N
HO2C
Me
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Me
O
O
2a
(1 equiv)
1A
(1.5 equiv)
3aA
Entry
1
[Pd]
Ligand
Base
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Solvent
Yield (%)b
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PCy3•HBF4
PCy3•HBF4
PCy3•HBF4
PMetBu2•HBF4
PtBu3•HBF4
XantPhos
1,4-Dioxane
DMAc
70
9
2
3
Toluene
65
41
54
11
4
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
5
6
7
PCy3•HBF4
PCy3•HBF4
PCy3•HBF4
PCy3•HBF4
PCy3•HBF4
PCy3•HBF4
36
--
8
Ag2CO3
DBU
9
27
73c
89d
80e
10
11
12
Cs2CO3
Cs2CO3
Cs2CO3
aReaction conditions: 2a (1 equiv), 1A (1.5 equiv), Pd(OAc)2 (10 mol%), ligand (20 mol%),
Cs2CO3 (3 equiv), solvent (1 mL), in a sealed tube and under N2 at 110 °C for 3 h. Isolated
b
yield. c0.3 equiv of PivOH was added. d1.5 equiv of 2a. eunder air.
We were pleased to find that by switching the amount ratio of ortho-iodoallenamide
2a from 1.0 equiv to 1.5 equiv, it increased the yield from 73% to 89% (Entry 11). It is
noteworthy that the presence of air did not affect the efficiency of the domino reaction
(Entry 12) and only one regioisomer was identified. Under these optimized conditions, we
demonstrated that this domino allylic alkynylation sequence could be successfully
performed from the ortho-bromoallenamide leading to 3aA in moderate yield (46%).
However, no reaction occurred from the ortho-chloroallenamide. Finally, the optimized
protocol was also easily scaled up from 0.41 to 3.65 mmol without a significant decrease in
yield (83%).
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Pd(OAc)2 (10 mol%)
PCy3HBF4 (20 mol%)
Cs2CO3 (2 equiv)
PivOH (30 mol%)
1,4-dioxane, 110°C, 3h
R2

I
R2
R1
R1
+
N
HO2C
N
Me
Me
O
O
3
2a-f
2A:
1A-J
(1.5 equiv)
(1 equiv)
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
R3
TIPS
N
N
CH3
N
N
N
CH3
CH3
CH3
O
O
O
O
3
3aB
3aC
3aD
3aE
74%
, R = 2-Naph
3
89%
85%
83%
64%
80%
, R = 3,4-di-MeO
3
, R = 2-CH3
3aH,
3aI,
3aJ,
73%
76%
80%
3
, R = 4-Cl
3
3aF
, R = 4-CF3
3
3aG
, R = 4-F
2B:

R3
Ph
TIPS
R1
R1
R1
N
N
CH3
CH3
N
CH3
O
O
O
1
3
3dK
3eC
3fL
74%
78%
79%
, R = 7-Cl, R = 4-CH3
, R1 = 5-CH3 73%
, R =6,7-di-Me 59%
1
3bA
3cA
3gI
3cI
1
3
, R = 6-CF3, R = 3,4-di-Me
, R = 7-CH3, R3 = 4-Ph
1
1
, R = 7-F
75%
, R =7-F
81%
1
Scheme 2. Scope of the Pd-catalyzed domino carbopalladation / decarboxylative allylic
alkynylation with various substituted ortho iodo-propa-1,2-dienylarylamides and alkynyl
carboxylic acids.
With the optimized conditions in hand, we set out to probe the scope of this Pd-
catalyzed domino reaction with various ortho-iodoallenamides 2a-f and alkynyl propiolic
acids 1A-J (Scheme 2). As shown in scheme 2A, a variety of aryl propiolic acids 1A-G was
investigated in presence of ortho-iodoallenamide 2a. Both electron rich and electron
deficient aryl propiolic acids reacted in moderate to good yields whatever the position of the
substituent on the aromatic moiety. Importantly, these conditions proved to be compatible
with the presence of cyclohexyl alkyne (76%), 2-pyridine alkyne (73%) and alkyne substituted
by TIPS as functional group (80%). Additionally, the Pd-catalyzed carbopalladation /
decarboxylative allylic alkynylation with other ortho-iodoallenamide derivatives (2b-g) was
investigated as illustrated in Scheme 2B. Various 2-iodo-N-(propa-1,2-dienyl)arylamides 2a-g
with either electron-donating or electron-withdrawing groups on the benzene ring displayed
high reactivity under the optimized reaction conditions. Overall, the selective capturing of
the π–allylpalladium intermediate with alkynyl carboxylic acids 1 was successfully achieved
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whatever the electronic effect and the position of substituents on both aromatic units of
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coupling partners 2 and 1, affording alkynylated isoquinolone 3b-g in fair yields.
R2
 One-pot isomerization / decarboxylative allylation
8
9
1) tBuOK (30 mol%)
I
R2
1,4-dioxane, r.t., 5 min.
R1
R1
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N
HO2C
N
2) Pd(OAc)2 (10 mol%)
PCy3HBF4 (20 mol%)
Cs2CO3 (2 equiv)
PivOH (30 mol%)
1,4-dioxane, 110 °C, 3 h
Me
Me
O
O
4a-h
(1.5 equiv)
1A-I
(1 equiv)
3
OMe
OMe
TIPS
N
F
Me
N
N
Me
Me
O
O
3aA,
O
3aC
3cI
, 81%
67%
, 74%
Scheme 3. Scope of the one-pot tBuOK-mediated allenamide generation followed by Pd-
catalyzed domino carbopalladation / decarboxylative allylic alkynylation
t
Based on our previously developed strategy of one-pot sequential BuOK-catalyzed
allenamide generation / Pd-domino C-H coupling,13, 18 we next envisioned generating
allenamide in a similar manner followed by the capture of the π–allylpalladium intermediate
with alkynyl carboxylic acids, all in a one-pot sequence (Scheme 3). This one-pot strategy
was immediately conclusive, providing the expected product 3aA in a fair 67% yield close to
the overall 73% yield obtained through the two-step sequential pathway. To showcase the
synthetic utility of this one-pot process based upon the in situ generation of the allenamide
2, we applied this approach to the synthesis of two other alkynylated isoquinolones 3aC and
3cl, which were are obtained with yields between 74% and 81% respectively (Scheme 3).
To further expand the scope of our methodology, we investigated the construction /
alkynylation of another family of heterocycles containing one nitrogen, indoles (Scheme 4).
Indoles are omnipresent in various bioactive compounds of alkaloids as well as
agrochemicals and pharmaceuticals.19 Based on the results developed above, another family
of iodoallenamide (6) precursors of indoles was evaluated in presence of various alkynyl
carboxylic acids 1. We were pleased to find that the optimized conditions developed above
were conclusive since the desired product 7aA was obtained in 78% yield (Scheme 4).
Therefore, various substituted heteroaryl propolic acids were then tested with this substrate
(6a) to examine the generality of this method for the formation of the alkynylated indoles
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7aJ and 7aM, which were obtained in moderate to good yields. Finally, we observed that the
electronic effect and the position of substituents on the aromatic units of coupling partners
6 and 1 did not influence the efficiency of the Pd-catalyzed construction / decarboxylation
allylic alkynalation, since fair yields were obtained for the synthesis of the expected C3-
alkynylated indoles 7bL, 7bC, 7cE and 7bl.
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Pd(OAc)2 (10 mol%)
PCy3HBF4 (20 mol%)
Cs2CO3 (2 equiv)
PivOH (30 mol%)
R2
I
R2
1,4-dioxane, 110 °C, 3 h

R1
R1
+
HO2C
N
Boc
N
Boc
6a-c
(1.5 equiv)
1A-M
(1 equiv)
7
R3
R3
TIPS
Cl
H3C
N
Boc
N
Boc
N
Boc
, R3 = H
7aA
7aJ
78%
57%
78%
, R3 = 4-Ph
80%
, R2 = 4-ClC6H4 92%
73%
7bL
7cE
7cI
, R3 = 2-pyr
, R3 = 4-OMe
, R3 = 3,4-diMeO 61%
, R2 = TIPS
7bC
7aM
Scheme 4. Extension to the indole scaffold.
Based on previous reports on cyclocarbo-palladation with allenamides,2 a catalytic
cycle is proposed as depicted in Scheme 5. The catalytic cycle is initiated by the oxidative
addition of allenamide 2 by the ligated Pd(0) species, generating the Pd(II) complex A. This is
followed by intramolecular cyclocarbopalladation to form the π-allylpalladium intermediate
B, which then rapidly undergoes an exothermic inner-sphere pivalate-halide exchange.17,20
The resulting more stable and less electron-rich η3-allylpalladium C is afterward involved in
the decarboxylative allylic alkynylation C. To date, two possible ways for the decarboxylation
of phenylpropiolic acid are considered:21 (1) in situ decarboxylation of the propiolic acid and
then the decarboxylated alkyne reacts with the palladium complex C (outer-sphere
mechanism or SN2’);22 (2) the propiolic acid reacts with the palladium complex C to produce
the phenyl propiolate palladium complex D before the decarboxylation step (inner-sphere
mechanism).23 Based on previous results observed by Grigg,3a-b the SN2’-type attack on the
(π-allyl)Pd complex, a charge-controlled outer sphere mechanism, can be precluded because
it favors an α-attack leading to the branched product. Moreover, it is noteworthy that this
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outer sphere nucleophilic attack was favored in presence of the cationic (π-allyl)Pd complex.
In the present case, the employment of pivalate combined with PCy3•HBF4, an electron-rich
phosphine, as ligand significantly decreased the positive charge of the (π-allyl)Pd complex C.
To gain deeper insight into the underlying mechanism, an experiment with phenylpropiolic
acid 1a with Cs2CO3 in 1,4 dioxane at 100 °C was conducted, and only the phenylpropiolic
acid was recovered. Thus, we can hypothesize that cesium phenylacetylenide is not directly
involved in the catalytic cycle. Together with the control experiment as well as previous
mechanism studies, we propose the following reaction mechanism through the formation of
the complex D before the decarboxylation step (Scheme 5).
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R2

X


N
CH3
N
2
CH3
O
4
O
Oxidative Addition
Pd0
Reductive
Elimination
X
Pd(II)

(II)
Pd

R
2
N

CH3
A
O
N
CH3
Carbopalladation
E
O
(II)
Pd

X
O
O
R2
-CO2
(II)
Pd


Decarboxylation
N
CH3

OCOtBu
Pd(II)

O
N

B
CH3
D
O
CsOCOtBu
CsX
N
HOCOtBu
CH3
C
O
R2
HO2C
Scheme 5. Proposed mechanistic pathway.
In summary, we have first reported an original and regioselective Pd-catalyzed domino
carbopalladation / decarboxylative allylic alkynylation of ortho–iodoallenamides (2) and (3)
with alkynyl carboxylic acids (1). This domino sequence was first validated and then applied
to the design of a novel library of 3-prop-2-yn-1-ylsoquinolin-1(2H)-ones, a key structural
motif with potential pharmaceutical significance.24 In parallel to this pathway, a one-pot
three-step strategy including the in situ generation of allenamide in the domino process was
also developed to avoid allenamide stability issues. This domino process tolerates various
functional groups, providing a synthetic tool to access isoquinolones and indoles bearing
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alkyne functionalities readily. Therefore, this construction / alkynylation methodology
involving the consecutive formation of C(sp2)-C(sp2) and C(sp3)-C(sp) bonds through trapping
a σ-allyl-Pd(II) intermediate with alkynyl carboxylic acids constitutes a straightforward and
general route to prepare a great variety of prop-2-ynyl frameworks.
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Experimental Section
Commercially available reagents were used throughout without further purification.
Reactions were routinely carried out under a nitrogen atmosphere using oven glassware.
Melting points were determined on a Fisher Scientific hot stage melting point apparatus and
1
are uncorrected. H and 13C NMR spectra were recorded using a Bruker Avance-300
spectrometer operating at 300 MHz (1H frequency, corresponding C and F frequencies
are 75 and 282 MHz). The chemical shifts are calibrated to residual proton and carbon
resonance of CDCl3 (1H 7.26 and 13C 77.1 ppm). In the 13C NMR spectra, signals
corresponding to CH, CH2, or CH3 groups are assigned from DEPT. The obtained signal
multiplicities were distinguished with the common abbreviations s (singlet), d (doublet), t
(triplet), q (quartet), bs (broad singlet), hep (heptet), sex (sextet) and the combinations
thereof. IR spectra were recorded on Perkin Elmer Spectrum 100 FT IR spectrometers. Low
resolution mass spectra analyses were performed with Jeol JMS-AX500 spectrometer in
chemical ionisation. HRMS were recorder on a LC Waters Acquity coupled to a Waters LCT
Premier XE instrument. Anhydrous 1,4-Dioxane, DMAc and DMF were purchased from
Sigma-Aldrich. THF and toluene were obtained by SPS purification. All reactions were
monitored by thin-layer chromatography with Merck silica gel 60 F254 pre-coated
aluminium plates (0.25 mm). Flash chromatography was carried out using Silicycle Siliaflash
P60 silica gel. Reversed-phase chromatography: Some purifications were carried out by flash
column chromatography system, Interchim®, puriflash 430, equipped with a dual UV-Vis
spectrophotometer (200–600 nm), a fraction collector (176 tubes), a dual piston pump (1 to
200 mL/min, Pmax = 30 bar) allowing quaternary gradients and an additional inlet for air
purge. Samples can be injected in solid mode, with dry loader, as celite® dry load. Using
Interchim® puriflash C18-HP 15µm F0004 (4 g) flash column.
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General procedure A:
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A flame-dried flask filled with argon was charged with the corresponding ortho halide
benzoic acid (1 eq.). This latter was dissolved in anhydrous CH2Cl2 (0.4 M) at 0°C under argon
atmosphere, following the dropwise addition of oxalylchloride (1.2 eq) and DMF (cat)
respectively. After 2 hours, the reaction mixture was warmed up to room temperature and
stirred for 2 h at room temperature. Once, the reaction cooled down to 0 °C, NEt3 (3 eq.) and
propargylamine (1.5 eq.) were then successively added dropwise. The reaction was warmed-
up to room temperature overnight. The reaction mixture was treated with aqueous solution
of NH4Cl and the layers were separated. The aqueous layer was then extracted with CH2Cl2
(3 times), and the combined organic layers were dried over MgSO4, filtrated and the solvent
was removed under reduced pressure. The crude product was then purified by flash
chromatography to obtain the corresponding propargylamide 4.25
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2-iodo-N,3-dimethyl-N-(prop-2-yn-1-yl)benzamide 4b: Compound 4b was prepared from 2-
iodo-3-methylbenzoic acid (3.82 mmol, 1eq.) according to the general procedure A
[oxalylchloride (4.58 mmol, 1.2 eq.), anhydrous DMF (0.2 mL), anhydrous CH2Cl2 (10 mL), N-
methylpropargylamine (5.73 mmol, 1.5 eq.), Et3N (11.5 mmol, 3 eq.)]. The crude product was
purified by flash chromatography (Et2O/PE 6:4) to afford 2-iodo-N,3-dimethyl-N-(prop-2-yn-
1-yl)benzamide 4b as yellow viscous oil (1.08 g) in 90% yield. Two rotamers were obtained.
1H NMR (300 MHz, CDCl3) δ 7.33 – 7.20 (m, 2H), 7.02 (ddd, J = 18.2, 7.2, 1.7 Hz, 1H), 4.43
(ddd, J = 23.4, 17.2, 2.4 Hz, 1H), 3.88 (ddd, J = 28.2, 17.8, 2.5 Hz, 1H), 3.20 (s, 1,24H), 2.90 (s,
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1,84H), 2.47 (s, 3H), 2.29 (t, J = 2.5 Hz, 1H). C{1H} NMR (75 MHz, CDCl3): δ 202.8 (C), 200.3
(C), 169.5 (C), 143.1 (C), 142.9 (C), 142.5 (C), 130.1 (CH), 130.0 (CH), 128.7 (CH), 125.0 (CH),
124.5 (CH), 102.5 (C), 99.6 (C), 99.3 (CH), 99.1 (CH), 87.5 (CH2), 87.3 (CH2), 34.6 (CH3), 30.7
(CH3), 28.9 (CH3), 28.9 (CH3). IR (neat) νmax 3046, 2925, 1959, 1641, 1381, 1324, 1066, 1011,
787 cm-1. MS (ESI) m/z 314.0030 [M+H]+. HMRS (ESI-TOF): [M+H]+ calc. for C12H13INO:
314.0042; found: 314.0030.
5-chloro-2-iodo-N-methyl-N-(prop-2-yn-1-yl)benzamide 4d: Compound 4d was prepared
from 5-chloro-2-iodobenzoic acid (3.76 mmol, 1eq.) according to the general procedure A
[oxalylchloride (4.51 mmol, 1.2 eq.), anhydrous DMF (0.2 mL), anhydrous CH2Cl2 (10 mL), N-
methylpropargylamine (5.64 mmol, 1.5 eq.), Et3N (11.3 mmol, 3 eq.)]. The crude product was
purified by flash chromatography (Et2O/PE 6:4) to afford 5-chloro-2-iodo-N-methyl-N-(prop-
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2-yn-1-yl)benzamide 4d as yellow viscous oil (727 mg) in 58% yield. Two rotamers were
obtained. 1H NMR (300 MHz, CDCl3) δ 7.6 (m, 1H), 7.40 (t, J = 2.0 Hz, 0.4H), 7.37 (t, J = 2.4 Hz,
0.6H), 7.25 (m, 1H), 4.41 (s, 1.25H), 3.89 (dd, J = 4.4, 2.4 Hz, 0.75H), 3.19 (s, 1.1H), 2.92 (s,
1.9H), 2.30 (m, 1H). 13C{1H} NMR (75 MHz, CDCl3): δ 168.1 (C), 168.1 (C), 136.4 (C), 135.9 (C),
135.9 (C), 135.7 (C), 132.7 (CH), 132.4 (CH), 128.7 (CH), 128.9 (CH), 128.5 (CH), 128.2 (CH),
119.8 (C), 119.7 (C), 77.6 (CH), 77.6 (CH), 73.8 (C), 72.2 (C), 40.6 (CH2), 37.1 (CH2), 35.3 (CH3),
32.3 (CH3). IR (neat) νmax 3291, 2935, 2140, 1645, 1403, 1091, 639, 522 cm-1. MS (ESI) m/z
333.9417 [M+H]+. HMRS (ESI-TOF): [M+H]+ calc. for C11H10ClINO: 333.9425; found: 333.9417.
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General procedure B (Synthesis of allenamide by using NaOH):
A flame-dried flask filled with argon was charged with corresponding ortho halide
propargylamide (1 eq.), and flask was closed by a septum. Back-filled with a flow of argon.
Argon atmosphere was ensured by argon balloon. Solid was dissolved in DMF (5-30 mL), and
stirred, then sodium hydroxide (1.2 eq.) was added quickly. After 12 hours, solution was
neutralized with adding of saturated solution of ammonium chloride (20-40 mL) and the
aqueous phase was extracted with CH2Cl2 (3 times). The combined organic phases were
dried with MgSO4, filtrated and the solvent was removed under reduced pressure. The crude
product was then purified by flash column chromatography to obtain corresponding ortho-
halide allenamide 2.25
2-iodo-N,3-dimethyl-N-(propa-1,2-dien-1-yl)benzamide 2b: Compound 2b was prepared
from propargylamide 5b (5.43 mmol, 1 eq.) according to the general procedure B [NaOH
(7.03 mmol, 1.2 eq.), and DMF (10 mL)]. The crude product was purified by flash
chromatography (Et2O/PE 1:1) to afford 2-iodo-N,3-dimethyl-N-(propa-1,2-dien-1-
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yl)benzamide 2b as yellow viscous oil (1.45 g) in 85% yield as a mixture of two rotamers. H
NMR (300 MHz, CDCl3) δ 7.70 (t, J = 6.3 Hz, 0.41H), 7.34 – 7.21 (m, 2.24H), 7.04 – 6.97
(m,1H), 6.39 (t, J = 6.3 Hz, 0.59H), 5.46 (dd, J = 6.4, 2.4 Hz, 0.76H), 5.37 (dd, J = 6.1, 5.3 Hz,
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2H), 3.18 (s, 1.71H), 2.85 (s, 1.19H), 2.48 (s, 3H). C{1H} NMR (75 MHz, CDCl3): δ 202.8 (C),
200.3 (C), 169.5 (C), 143.1 (C), 142.9 (C), 142.5 (C), 130.1 (CH), 130.0 (CH), 128.7 (CH), 125.0
(CH), 124.5 (CH), 102.5 (C), 99.6 (C), 99.3 (CH), 99.1 (CH), 87.5 (CH2), 87.3 (CH2), 34.6 (CH3),
30.7 (CH3), 28.9 (CH3), 28.9 (CH3). IR (neat) νmax 3046, 2925, 1959, 1641, 1381, 1324, 1066,
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1011, 787 cm-1. MS (ESI) m/z 314.0030 [M+H]+. HMRS (ESI-TOF): [M+H]+ calc. for C12H13INO:
314.0042; found: 314.0030.
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5-chloro-2-iodo-N-methyl-N-(propa-1,2-dien-1-yl)benzamide 2d: Compound 2d was
prepared from propargylamide 4b (1.28 mmol, 1 eq.) according to the general procedure B
[NaOH (1.54 mmol, 1.2 eq.), and DMF (2.2 mL)]. The crude product was purified by flash
chromatography (EtOAc/PE 2:8) to afford 5-chloro-2-iodo-N-methyl-N-(propa-1,2-dien-1-
yl)benzamide 2d as yellow solid (200 mg) in 47% yield as a mixture of two rotamers. 1H NMR
(300 MHz, CDCl3) δ 7.61 (t, J = 6.4 Hz, 0.4H), 7.50 (dd, J = 8.4, 2.7 Hz, 1H), 7.31 – 7.18 (m, 2H),
6.34 (t, J = 6.2 Hz, 0.6H), 5.45 (d, J = 6.4 Hz, 1H), 5.37 (dd, J = 6.2, 1.8 Hz, 1H), 3.14 (s, 1.7H),
2.86 (s, 1.3H). 13C{1H} NMR (75 MHz, CDCl3) δ 202.7 (C), 200.4 (C), 166.5 (C), 136.2 (C), 136.0
(C), 135.7 (C), 132.9 (CH), 132.7 (CH), 129.3 (CH), 129.0 (CH), 128.3 (CH), 120.2 (C), 119.9 (C),
102.1 (CH), 99.2 (CH), 87.7 (CH2), 87.6 (CH2), 34.4 (CH3), 30.9 (CH3). IR (neat) νmax 3224, 3130,
2932, 1635, 1408, 1371, 882 cm-1. MS (ESI) m/z 333.9501 [M+H]+. HMRS (ESI-TOF): [M+H]+
calc. for C11H10ClINO: 333.9496; found: 333.9501.
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General procedure C (Synthesis of allenamide 6 by using tBuOK):
A flame-dried flask filled with argon was charged with corresponding ortho halide carbamate
5 (1 eq.), and flask was closed by a septum. Back-filled with a flow of argon. Argon
atmosphere was ensured by argon balloon. Solid was dissolved in THF, and stirred and
cooled to -78 °C, then potassium tert-butoxide (2 eq.) was added quickly. After 2 hours,
solution was neutralized by adding of saturated solution of ammonium chloride (20-40 mL)
and the aqueous phase was extracted with CH2Cl2 (3 times). The combined organic phases
were dried with MgSO4, filtrated and the solvent was removed under reduced pressure. The
crude product was then purified by flash chromatography to obtain corresponding
allenamide 6.25
tert-butyl (4-chloro-2-iodophenyl)(propa-1,2-dien-1-yl)carbamate 6b: Compound 6b was
prepared from propargylamide 5b (7.8 mmol, 1 eq.) according to the general procedure C [t-
BuOK (14.47 mmol, 2 eq.), and THF (50 mL)]. The crude product was purified by flash
chromatography (Et2O/PE 1:99) to afford tert-butyl (4-chloro-2-iodophenyl)(propa-1,2-dien-
1-yl)carbamate 6b as white solid (2.53 g) in quantitative yield as a mixture of two rotamers.
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mp 90 °C (CH2Cl2). 1H NMR (300 MHz, CDCl3) δ 7.81 (s, 1H), 7.34 – 7.21 (m, 1.7H), 7.18 – 7.05
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(m, 1.3H), 5.07 – 4.95 (m, 2H), 1.55 (s, 2.3H), 1.37 (s, 6.7H). C{1H} NMR (75 MHz, CDCl3) δ
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201.4 (C), 200.3 (C), 151.1 (C), 140.7 (C), 138.9 (CH), 138.7 (CH), 134.1 (C), 133.7 (C), 130.6
(CH), 130.1 (CH), 129.2 (CH), 129.1 (CH), 101.5 (CH), 100.9 (CH), 99.9 (C), 87.3 (CH2), 86.9
(CH2), 82.5 (C), 81.9 (C), 28.3 (CH3), 28.1 (CH3). IR (neat) νmax 3061, 2976, 2929, 1699, 1360,
1318, 1159, 1070, 855 cm-1. MS (ESI) m/z 391.9899 [M+H]+. HMRS (ESI-TOF): [M+H]+ calc. for
C14H16IClNO2: 391.9914; found: 391.9899.
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tert-butyl (2-iodo-4-methylphenyl)(propa-1,2-dien-1-yl)carbamate 6c: Compound 6c was
prepared from propargylamide 5c (1.86 mmol, 1 eq.) according to the general procedure C
[t-BuOK (3.71 mmol, 2 eq.), and THF (20 mL)]. The crude product was purified by flash
chromatography (Et2O/PE 1:99) to afford tert-butyl (2-iodo-4-methylphenyl)(propa-1,2-dien-
1-yl)carbamate 6c as white solid (400 mg) in 58% yield as a mixture of two rotamers. mp 76 -
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78 °C (CH2Cl2). H NMR (300 MHz, CDCl3) δ 7.66 (s, 1H), 7.32 – 7.22 (m, 0.75H), 7.08 (dd, J =
24.2, 6.9 Hz, 2.25H), 5.07 – 4.93 (m, 2H), 2.31 (s, 3H), 1.56 (s, 2.65H), 1.37 (s, 6.35H). 13C{1H}
NMR (75 MHz, CDCl3) δ 201.8 (C), 200.7 (C), 151.7 (C), 140.0 (CH), 139.7 (CH), 139.3 (C),
130.0 (CH), 129.7 (CH), 129.6 (CH), 129.0 (CH), 101.8 (CH), 101.3 (CH), 99.4 (C), 86.9 (CH2),
86.5 (CH2), 82.2 (C), 81.5 (C), 28.4 (CH3), 28.3 (CH3), 20.7 (CH3). IR (neat) νmax 3053, 2978,
2930, 1690, 1369, 1318, 1158, 850, 760 cm-1. MS (ESI) m/z 372.0470 [M+H]+. HMRS (ESI-
TOF): [M+H]+ calc. for C15H19INO2: 372.0460; found: 372.0470.
General procedure D: Cascade reaction with propiolic acid decarboxylation, and isolated
allenamides: In an oven-dried screwcaped sealed tub, under dried nitrogen and containing
a magnetic stir bar, ortho-iodoallenamide 2 (1.5 eq.), propiolic acid 1 (1 eq.), Pd(OAc)2 (10
mol%.), PCy3•HBF4 (20 mol%), Cs2CO3 (2 eq.), and pivalic acid (0.3 eq.) were added
respectively. Container was back-filled with a flow of dried nitrogen. Anhydrous solvent (1.5
mL) was added, and the tub was sealed and then warmed up to 110°C for 3 hours. After
filtration on Celite® and concentration under vacuum, the crude product was purified by
flash column chromatography on silica gel to the give desired pure product.
General procedure E: Cascade reaction with propiolic acid decarboxylation, and in situ
generation of allenamides: In an oven-dried screwcaped sealed tub, under dried nitrogen
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and containing a magnetic stir bar. t-BuOK (0.3 eq.) was added to a solution of
propargylamide 4 (1.5 eq.) in 1,4-dioxane (0.123M) and then mixture was stirred for 4 min.
The crude mixture was quenched with PivOH (0.3 eq.), and the resulting solution was stirred
for 1 min at room temperature. Then, alkynyl carboxylic acid 1 (1 eq.), Pd(OAc)2 (10 mol%.),
PCy3•HBF4 (20 mol%), Cs2CO3 (3 eq.), and 1,4-Dioxane were added. The tube was sealed, and
warmed up to 110°C for 3 hours. After filtration on Celite® and concentration under vacuum,
the crude product was purified by flash column chromatography on silica gel to give the
desired pure product.
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2-methyl-4-(3-phenylprop-2-yn-1-yl)isoquinolin-1(2H)-one 3aA: Compound 3aA was
prepared according to the general procedure D: [acid 1A (0.41 mmol, 1 eq.), allenamide 2a
(0.615 mmol, 1.5 eq.), Pd(OAc)2 (0.041 mmol, 0.1 eq.), PCy3•HBF4 (0.082 mmol, 0.2 eq.),
Cs2CO3 (0.82 mmol, 2 eq.), PivOH (0.123 mmol, 0.3 eq.) 1,4-dioxane (1.5 mL)]. The crude
product was purified by flash chromatography (EtOAc/PE 3:7) to afford the product 3aA as a
orange solid (95 mg) in 95% yield.
Compound 3aA was prepared according to the general procedure E: [t-BuOK (0.123 mmol,
0.3 eq.) and 1,4-dioxane (2 x 0.5mL), then PivOH (0.123 mmol, 0.3 eq.) and then acid 1A
(0.41 mmol, 1 eq.), 2-iodo-N-methyl-N-(prop-2-yn-1-yl)benzamide 4a (0.615 mmol, 1.5 eq.),
Pd(OAc)2 (0.041 mmol, 0.1 eq.), PCy3•HBF4 (0.082 mmol, 0.2 eq.), Cs2CO3 (0.82 mmol, 2 eq.),
1,4-dioxane (1.5 mL)]. The crude product was purified by flash chromatography (EtOAc/PE
3:7) to afford the product 3aA as a orange solid (75 mg) in 67% yield. mp = 112 – 113 °C
(Et2O/PE); 1H NMR (300 MHz, CDCl3): δ 8.46 (d, J = 8.0 Hz, 1H), 7.68 – 7.61 (m, 2H), 7.48 (ddd,
J = 8.1, 6.0, 2.2 Hz, 1H), 7.41 (dd, J = 6.6, 2.9 Hz, 2H), 7.30 – 7.24 (m, 3H), 7.18 (s, 1H), 3.77 (s,
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2H), 3.56 (s, 3H); C{1H} NMR (75 MHz, CDCl3): δ 162.4 (C), 136.0 (C), 132.2 (CH), 131.7
(2xCH), 131.0 (CH), 128.4 (2xCH), 128.4 (CH), 128.2 (CH), 127.0 (CH), 126.0 (C), 123.2 (C),
122.4 (CH), 111.1 (C), 85.9 (C), 84.0 (C), 37.1 (CH3), 20.4 (CH2); IR (neat) νmax 3060, 3034,
2910, 1624, 1593, 762, 693 cm-1; MS (ESI) m/z 274.1233 [M+H]+; HMRS (ESI-TOF): [M+H]+
calc. for C19H16NO: 274.1232; found: 274.1233.
2-methyl-4-(3-(naphthalen-2-yl)prop-2-yn-1-yl)isoquinolin-1(2H)-one 3aB: Compound 3aB
was prepared according to the general procedure D: [acid 1B (0.41 mmol, 1 eq.), allenamide
2a (0.615 mmol, 1.5 eq.), Pd(OAc)2 (0.041 mmol, 0.1 eq.), PCy3•HBF4 (0.082 mmol, 0.2 eq.),
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Cs2CO3 (0.82 mmol, 2 eq.), PivOH (0.123 mmol, 0.3 eq.) 1,4-dioxane (1.5 mL)]. The crude
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product was purified by flash chromatography (EtOAc/PE 3:7) to afford the product 3aB as a
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yellow solid (98 mg) in 74% yield. mp = 148 °C (Et2O/PE); H NMR (300 MHz, CDCl3): δ 8.32
(d, J = 8.0 Hz, 1H), 7.75 (s, 1H), 7.58 (t, J = 8.7 Hz, 3H), 7.51 (d, J = 3.7 Hz, 2H), 7.34 (dd, J = 8.2
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and 4.0 Hz, 1H), 7.28 (d, J = 6.4 Hz, 3H), 7.06 (s, 1H), 3.66 (s, 2H), 3.42 (s, 3H); C{1H} NMR
(75 MHz, CDCl3): δ 162.4 (C), 136.0 (C), 133.0 (C), 132.8 (C), 132.2 (CH), 131.5 (CH), 131.1
(CH), 128.6 (CH), 128.4 (CH), 128.1 (CH), 127.8 (CH), 127.7 (CH), 127.0 (CH), 126.7 (CH), 126.7
(CH), 126.1 (C), 122.4 (CH), 120.5 (C), 111.1 (C), 86.3 (C), 84.3 (C), 37.2 (CH3), 20.5 (CH2); IR
(neat) νmax 3053, 2923, 1624, 1592, 817, 756, 692, 475 cm-1; MS (ESI) m/z 324.1385 [M+H]+.
HMRS (ESI-TOF): [M+H]+ calc. for C23H18NO: 324.1388; found: 324.1385.
4-(3-(3,4-dimethoxyphenyl)prop-2-yn-1-yl)-2-methylisoquinolin-1(2H)-one 3aC: Compound
3aC was prepared according to the general procedure D [acid 1C (0.41 mmol, 1 eq.),
allenamide 2a (0.615 mmol, 1.5 eq.), Pd(OAc)2 (0.041 mmol, 0.1 eq.), PCy3•HBF4 (0.082
mmol, 0.2 eq.), Cs2CO3 (0.82 mmol, 2 eq.), PivOH (0.123 mmol, 0.3 eq.) 1,4-dioxane (1.5
mL)]. The crude product was purified by flash chromatography (EtOAc/PE 4:6) to afford the
product 3aC as a yellow solid (121 mg) in 89% yield.
Compound 3aC was prepared according to the general procedure E: [t-BuOK (0.123 mmol,
0.3 eq.) and 1,4-dioxane (2 x 0.5mL), then PivOH (0.123 mmol, 0.3 eq.) and then acid 1C
(0.41 mmol, 1 eq.), 2-iodo-N-methyl-N-(prop-2-yn-1-yl)benzamide 4a (0.615 mmol, 1.5 eq.),
Pd(OAc)2 (0.041 mmol, 0.1 eq.), PCy3•HBF4 (0.082 mmol, 0.2 eq.), Cs2CO3 (0.82 mmol, 2 eq.),
1,4-dioxane (1.5 mL)]. The crude product was purified by flash chromatography (EtOAc/PE
4:6) to afford the product 3aC as a yellow solid (105 mg) in 74% yield. mp = 121 °C (Et2O/PE);
1H NMR (300 MHz, CDCl3): δ 8.47 (d, J = 8.0 Hz, 1H), 7.70 – 7.64 (m, 2H), 7.50 (ddd, J = 8.1,
5.4 and 2.9 Hz, 1H), 7.21 (s, 1H), 7.02 (dd, J = 8.2 and 1.6 Hz, 1H), 6.92 (d, J = 1.5 Hz, 1H), 6.77
(d, J = 8.3 Hz, 1H), 3.85 (s, 3H), 3.84 (s, 3H), 3.78 (s, 2H), 3.59 (s, 3H); C{1H} NMR (75 MHz,
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CDCl3): δ 162.4 (C), 149.4 (C), 148.6 (C), 136.0 (C), 132.2 (CH), 130.9 (CH), 128.3 (CH), 126.9
(CH), 125.9 (C), 124.9 (CH), 122.4 (CH), 115.4 (C), 114.3 (CH), 111.2 (C), 111.0 (CH), 84.2 (C),
83.8 (C), 55.9 (3xCH3), 37.1 (CH3), 20.4 (CH2); IR (neat) νmax 2934, 2839, 1656, 1626, 1599,
1512, 1239, 1137, 1022, 763 cm-1; MS (ESI) m/z 334.1446 [M+H]+. HMRS (ESI-TOF): [M+H]+
calc. for C21H20NO3: 334.1443; found: 334.1446.
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2-methyl-4-(3-(o-tolyl)prop-2-yn-1-yl)isoquinolin-1(2H)-one 3aD: Compound 3aD was
prepared according to the general procedure D: [acid 1D (0.41 mmol, 1 eq.), allenamide 2a
(0.615 mmol, 1.5 eq.), Pd(OAc)2 (0.041 mmol, 0.1 eq.), PCy3•HBF4 (0.082 mmol, 0.2 eq.),
Cs2CO3 (0.82 mmol, 2 eq.), PivOH (0.123 mmol, 0.3 eq.) 1,4-dioxane (1.5 mL)]. The crude
product was purified by flash chromatography (EtOAc/PE 4:6) to afford the product 3aD as a
yellow solid (101 mg) in 86% yield. mp = 128 – 129 °C (Et2O/PE); 1H NMR (300 MHz, CDCl3): δ
8.53 (dt, J = 8.0 and 1.1 Hz, 1H), 7.75 – 7.71 (m, 2H), 7.59 – 7.53 (m, 1H), 7.44 (dd, J = 7.2 and
1.2 Hz, 1H), 7.29 (s, 1H), 7.25 – 7.21 (m, 2H), 7.20 – 7.12 (m, 1H), 3.89 (d, J = 1.2 Hz, 2H), 3.63
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(s, 3H), 2.44 (s, 3H); C{1H} NMR (75 MHz, CDCl3): δ 162.4 (C), 140.1 (C), 136.0 (C), 132.1
(CH), 132.0 (CH), 130.9 (CH), 129.5 (CH), 128.3 (CH), 128.2 (CH), 127.0 (CH), 126.0 (C), 125.6
(CH), 123.0 (C), 122.5 (CH), 111.3 (C), 89.7 (C), 82.9 (C), 37.1 (CH3), 20.9 (CH3), 20.6 (CH2); IR
(neat) νmax 3066, 2972, 1655, 1626, 1489, 1082, 760 cm-1; MS (ESI) m/z 288.1397 [M+H]+.
HMRS (ESI-TOF): [M+H]+ calc. for C20H18NO: 288.1388; found: 288.1397.
4-(3-(4-chlorophenyl)prop-2-yn-1-yl)-2-methylisoquinolin-1(2H)-one 3aE: Compound 3aE
was prepared according to the general procedure D: [acid 1E (0.41 mmol, 1 eq.), allenamide
2a (0.615 mmol, 1.5 eq.), Pd(OAc)2 (0.041 mmol, 0.1 eq.), PCy3•HBF4 (0.082 mmol, 0.2 eq.),
Cs2CO3 (0.82 mmol, 2 eq.), PivOH (0.123 mmol, 0.3 eq.) 1,4-dioxane (1.5 mL)]. The crude
product was purified by flash chromatography (EtOAc/PE 4:6) to afford the product 3aE as a
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yellow/orange solid (96 mg) in 80% yield. mp = 124 – 126 °C (Et2O/PE); H NMR (300 MHz,
CDCl3): δ 8.43 (d, J = 8.1 Hz, 1H), 7.67 – 7.57 (m, 2H), 7.46 (ddd, J = 8.2, 6.1 and 2.2 Hz, 1H),
7.28 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 8.3 Hz, 2H), 7.14 (s, 1H), 3.74 (d, J = 1.2 Hz, 2H), 3.55 (s,
3H); 13C{1H} NMR (75 MHz, CDCl3): δ 162.5 (C), 136.0 (C), 134.3 (C), 133.0 (2xCH), 132.3 (CH),
131.1 (CH), 128.8 (2xCH), 128.5 (CH), 127.1 (CH), 126.1 (C), 122.4 (CH), 121.8 (C), 110.9 (C),
87.0 (C), 82.8 (C), 37.2 (CH3), 20.5 (CH2); IR (neat) νmax 3066, 2960, 1656, 1627, 1601, 833,
761 cm-1; MS (ESI) m/z 308.0850 [M+H]+. HMRS (ESI-TOF): [M+H]+ calc. for C19H15NOCl:
308.0842; found: 308.0850.
2-methyl-4-(3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-yl)isoquinolin-1(2H)-one
3aF :
Compound 3aF was prepared according to the general procedure D: [acid 1F (0.41 mmol, 1
eq.), allenamide 2a (0.615 mmol, 1.5 eq.), Pd(OAc)2 (0.041 mmol, 0.1 eq.), PCy3•HBF4 (0.082
mmol, 0.2 eq.), Cs2CO3 (0.82 mmol, 2 eq.), PivOH (0.123 mmol, 0.3 eq.) 1,4-dioxane (1.5
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mL)]. The crude product was purified by flash chromatography (EtOAc/PE 3:7) to afford the
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product 3aF as a yellow solid (89 mg) in 64% yield. mp = 131.5 – 132 °C (Et2O/PE); H NMR
(300 MHz, CDCl3): δ 8.50 (d, J = 7.9 Hz, 1H), 7.70 (d, J = 6.3 Hz, 2H), 7.59 – 7.47 (m, 5H), 7.20
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(s, 1H), 3.83 (s, 2H), 3.61 (s, 3H); C{1H} NMR (75 MHz, CDCl3): δ 162.4 (C), 135.9 (C), 132.3
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(CH), 132.0 (2xCH), 131.1 (CH), 130.0 (q, J = 32.7 Hz, C), 128.4 (CH), 127.1 (CH), 126.1 (C),
125.3 (q, J = 3.8 Hz, CH), 124.0 (q, J = 272.2 Hz, C) 122.4 (CH), 110.7 (C), 88.8 (C), 82.6 (C),
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37.2 (CH3), 20.5 (CH2); F NMR (282 MHz, CDCl3) δ -62.77; IR (neat) νmax 3060, 2905, 1627,
1604, 1323, 1106, 1064, 846, 762, 693 cm-1; MS (ESI) m/z 342.1094 [M+H]+; HMRS (ESI-TOF):
[M+H]+ calc. for C20H15F3NO: 342.1106; found: 342.1094.
4-(3-(4-fluorophenyl)prop-2-yn-1-yl)-2-methylisoquinolin-1(2H)-one 3aG: Compound 3aG
was prepared according to the general procedure D: [acid 1G (0.41 mmol, 1 eq.), allenamide
2a (0.615 mmol, 1.5 eq.), Pd(OAc)2 (0.041 mmol, 0.1 eq.), PCy3•HBF4 (0.082 mmol, 0.2 eq.),
Cs2CO3 (0.82 mmol, 2 eq.), PivOH (0.123 mmol, 0.3 eq.) 1,4-dioxane (1.5 mL).] The crude
product was purified by flash chromatography (EtOAc/PE 4:6) to afford the product 3aG as a
yellow solid (105 mg) in 83% yield. mp = 138 – 139 °C (Et2O/PE); 1H NMR (300 MHz, CDCl3): δ
8.50 (d, J = 8.0 Hz, 1H), 7.75 – 7.64 (m, 2H), 7.52 (ddd, J = 8.2, 5.8 and 2.4 Hz, 1H), 7.45 – 7.35
(m, 2H), 7.21 (d, J = 1.4 Hz, 1H), 6.99 (t, J = 8.7 Hz, 2H), 3.80 (d, J = 1.2 Hz, 2H), 3.61 (s, 3H);
13C{1H} NMR (75 MHz, CDCl3): δ 162.5 (d, J = 249.2 Hz, C), 162.4 (C), 136.0 (C), 133.6 (d, J =
8.3 Hz, 2xCH), 132.2 (CH), 131.0 (CH), 128.4 (CH), 127.0 (CH), 126.1 (C), 122.4 (CH), 119.3 (d,
J = 3.5 Hz, C), 115.7 (d, J = 22.0 Hz, 2xCH), 111.0 (C), 85.6 (d, J = 1.5 Hz, C), 82.8 (C), 37.1
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(CH3), 20.4 (CH2); F NMR (282 MHz, CDCl3) δ -111.14; IR (neat) νmax 3060, 3040, 1625, 1600,
1505, 1215, 837 cm-1; MS (ESI) m/z 292.1138 [M+H]+; HMRS (ESI-TOF): [M+H]+ calc. for
C19H15FNO: 292.1138; found: 292.1138.
4-(3-cyclohexylprop-2-yn-1-yl)-2-methylisoquinolin-1(2H)-one 3aH: Compound 3aH was
prepared according to the general procedure D: [acid 1H (0.41 mmol, 1 eq.), allenamide 2a
(0.615 mmol, 1.5 eq.), Pd(OAc)2 (0.041 mmol, 0.1 eq.), PCy3•HBF4 (0.082 mmol, 0.2 eq.),
Cs2CO3 (0.82 mmol, 2 eq.), PivOH (0.123 mmol, 0.3 eq.) 1,4-dioxane (1.5 mL)]. The crude
product was purified by flash chromatography (EtOAc/PE 25:75) to afford the product 3aH
as a yellow solid (87 mg) in 76% yield. mp = 127.5 °C (Et2O/PE); 1H NMR (300 MHz, CDCl3): δ
8.52 – 8.44 (m, 1H), 7.72 – 7.59 (m, 2H), 7.50 (ddd, J = 8.2, 6.8 and 1.5 Hz, 1H), 7.21 (s, 1H),
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3.61 (s, 3H), 3.59 – 3.58 (m, 2H), 2.49 – 2.35 (m, 1H), 1.89 – 1.76 (m, 2H), 1.76 – 1.63 (m, 2H),
1.57 – 1.38 (m, 2H), 1.38 – 1.26 (m, 2H); 13C{1H} NMR (75 MHz, CDCl3): δ 162.4 (C), 136.1 (C),
132.0 (CH), 130.7 (CH), 128.2 (CH), 126.8 (CH), 125.8 (C), 122.3 (CH), 111.8, (C) 88.7 (C), 75.8
(C), 37.1 (CH3), 33.0 (2xCH2), 29.2 (CH3), 25.9 (CH2), 24.9 (CH2), 19.7 (2xCH2); IR (neat) νmax
3053, 2927, 2851, 1626, 1592, 1356, 758, 692 cm-1; MS (ESI) m/z 280.1696 [M+H]+; HMRS
(ESI-TOF): [M+H]+ calc. for C19H22NO: 280.1701; found: 280.1696.
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2-methyl-4-(3-(triisopropylsilyl)prop-2-yn-1-yl)isoquinolin-1(2H)-one 3aI: Compound 3aI
was prepared according to the general procedure D: [acid 1I (0.41 mmol, 1 eq.), allenamide
2a (0.615 mmol, 1.5 eq.), Pd(OAc)2 (0.041 mmol, 0.1 eq.), PCy3•HBF4 (0.082 mmol, 0.2 eq.),
Cs2CO3 (0.82 mmol, 2 eq.), PivOH (0.123 mmol, 0.3 eq.) 1,4-dioxane (1.5 mL)]. The crude
product was purified by flash chromatography (EtOAc/PE 2:8) to afford the product 3aI as a
yellow solid (116 mg) in 80% yield. mp = 109 °C (Et2O/PE); 1H NMR (300 MHz, CDCl3): δ 8.46
(d, J = 7.9 Hz, 1H), 7.65 (t, J = 7.0 Hz, 1H), 7.57 (d, J = 7.7 Hz, 1H), 7.48 (t, J = 7.5 Hz, 1H), 7.29
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(s, 1H), 3.66 (s, 2H), 3.58 (s, 3H), 1.08 (s, 21H); C{1H} NMR (75 MHz, CDCl3): δ 162.4 (C),
135.9 (C), 132.1 (CH), 131.0 (CH), 128.3 (CH), 126.9 (CH), 125.9 (C), 122.2 (CH), 110.9 (C),
104.0 (C), 85.1 (C), 37.1 (CH3), 20.9 (CH2), 18.7 (6xCH3), 11.3 (3xCH); IR (neat) νmax 2940,
2863, 2173, 1657, 1627, 759, 691, 674, 661, 643 cm-1; MS (ESI) m/z 354.2247 [M+H]+; HMRS
(ESI-TOF): [M+H]+ calc. for C22H32NOSi: 354.2253; found: 354.2247.
2-methyl-4-(3-(pyridin-2-yl)prop-2-yn-1-yl)isoquinolin-1(2H)-one 3aJ: Compound 3aJ was
prepared according to the general procedure D: [acid 1J (0.41 mmol, 1 eq.), allenamide 2a
(0.615 mmol, 1.5 eq.), Pd(OAc)2 (0.041 mmol, 0.1 eq.), PCy3•HBF4 (0.082 mmol, 0.2 eq.),
Cs2CO3 (0.82 mmol, 2 eq.), PivOH (0.123 mmol, 0.3 eq.) 1,4-dioxane (1.5 mL)]. The crude
product was purified by flash chromatography (EtOAc/PE 95:5) to afford the product 3aJ as a
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pale yellow solid (82 mg) in 73% yield. mp = 121 °C (Et2O/PE); H NMR (300 MHz, CDCl3): δ
8.72 (s, 1H), 8.60 – 8.50 (m, 2H), 7.78 – 7.72 (m, 3H), 7.58 (ddd, J = 8.1, 6.0, 2.0 Hz, 1H), 7.36
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– 7.25 (m, 1H), 7.26 (s, 1H), 3.89 (s, 2H), 3.67 (s, 3H); C{1H} NMR (75 MHz, CDCl3): δ 162.4
(C), 152.4 (CH), 148.6 (CH), 138.7 (CH), 135.9 (C), 132.3 (CH), 131.1 (CH), 128.4 (CH), 127.1
(CH), 126.1 (C), 123.1 (CH), 122.4 (CH), 120.4 (C), 110.6 (C), 89.6 (C), 80.5 (C), 37.1 (CH3), 20.5
(CH2); IR (neat) νmax 2925, 2854, 1647, 1623, 1313, 773, 696 cm-1; MS (ESI) m/z 275.1183
[M+H]+; HMRS (ESI-TOF): [M+H]+ calc. for C18H15N2O: 275.1184; found: 275.1183.
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2,5-dimethyl-4-(3-phenylprop-2-yn-1-yl)isoquinolin-1(2H)-one 3bA: Compound 3bA was
prepared according to the general procedure D: [acid 1A (0.41 mmol, 1 eq.), allenamide 2b
(0.615 mmol, 1.5 eq.), Pd(OAc)2 (0.041 mmol, 0.1 eq.), PCy3•HBF4 (0.082 mmol, 0.2 eq.),
Cs2CO3 (0.82 mmol, 2 eq.), PivOH (0.123 mmol, 0.3 eq.) 1,4-dioxane (1.5 mL)]. The crude
product was purified by flash chromatography (EtOAc/PE 3:7) to afford the product 3bA as a
yellow solid (86 mg) in 73% yield. mp = 115 – 117 °C (Et2O/PE); 1H NMR (300 MHz, CDCl3): δ
8.45 (dd, J = 7.9, 1.2 Hz, 1H), 7.48 – 7.35 (m, 4H), 7.33 – 7.27 (m, 3H), 7.21 (s, 1H), 4.02 (d, J =
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0.8 Hz, 2H), 3.59 (s, 3H), 2.89 (s, 3H); C{1H} NMR (75 MHz, CDCl3): δ 162.4 (C), 136.3 (CH),
135.5 (C), 133.7 (C), 132.3 (CH), 131.6 (2xCH), 128.4 (2xCH), 128.2 (CH), 127.6 (C), 127.1 (CH),
126.7 (CH), 123.3 (C), 112.1 (C), 87.4 (C), 84.3 (C), 36.9 (CH3), 24.8 (CH2), 23.9 (CH3); IR (neat)
νmax 3060, 3021, 2921, 1647, 1625, 774, 757, 697 cm-1; MS (ESI) m/z 288.1385 [M+H]+; HMRS
(ESI-TOF): [M+H]+ calc. for C20H18NO: 288.1388; found: 288.1385.
7-fluoro-2-methyl-4-(3-phenylprop-2-yn-1-yl)isoquinolin-1(2H)-one 3cA: Compound 3cA
was prepared according to the general procedure D: [acid 1A (0.41 mmol, 1 eq.), allenamide
2c (0.615 mmol, 1.5 eq.), Pd(OAc)2 (0.041 mmol, 0.1 eq.), PCy3•HBF4 (0.082 mmol, 0.2 eq.),
Cs2CO3 (0.82 mmol, 2 eq.), PivOH (0.123 mmol, 0.3 eq.) 1,4-dioxane (1.5 mL)]. The crude
product was purified by flash chromatography (EtOAc/PE 3:7) to afford the product 3cA as a
yellow solid (67 mg) in 32% yield. mp = 119 – 120 °C (Et2O/PE); 1H NMR (300 MHz, CDCl3): δ
8.14 (dd, J = 9.4 and 2.7 Hz, 1H), 7.73 (dd, J = 8.9 and 5.0 Hz, 1H), 7.49 – 7.39 (m, 3H), 7.35 –
7.28 (m, 3H), 7.20 (s, 1H), 3.82 (s, 2H), 3.62 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3): δ 161.7 (d,
J = 3.5 Hz, C), 161.7 (d, J = 247.9 Hz, C), 132.7 (d, J = 2.1 Hz, C), 131.8 (2xCH), 130.4 (d, J = 2.3
Hz, CH), 128.5 (2xCH), 128.4 (CH), 127.9 (d, J = 8.0 Hz, C), 125.0 (d, J = 7.8 Hz, CH), 123.2 (C),
120.9 (d, J = 23.5 Hz, CH), 113.6 (d, J = 22.7 Hz, CH), 110.9 (C), 85.6 (C), 84.1 (C), 37.2 (CH3),
20.7 (CH2); IR (neat) νmax 3060, 2925, 2858, 1657, 1629, 1615, 1504, 842, 751, 688, 405 cm-1;
19F NMR (282 MHz, CDCl3) δ -112.76 – -112.92 (m); MS (ESI) m/z 292.1137 [M+H]+; HMRS
(ESI-TOF): [M+H]+ calc. for C19H15FNO: 292.1138; found: 292.1137.
7-chloro-2-methyl-4-(3-(p-tolyl)prop-2-yn-1-yl)isoquinolin-1(2H)-one 3dK: Compound 3cK
was prepared according to the general procedure D: [acid 1K (0.41 mmol, 1 eq.), allenamide
2d (0.615 mmol, 1.5 eq.), Pd(OAc)2 (0.041 mmol, 0.1 eq.), PCy3•HBF4 (0.082 mmol, 0.2 eq.),
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Cs2CO3 (0.82 mmol, 2 eq.), PivOH (0.123 mmol, 0.3 eq.) 1,4-dioxane (1.5 mL)]. The crude
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pale yellow solid (97 mg) in 74% yield. mp = 157 – 158 °C (Et2O/PE); H NMR (300 MHz,
CDCl3): δ 8.41 (d, J = 8.6 Hz, 1H), 7.65 (d, J = 1.7 Hz, 1H), 7.45 (dd, J = 8.6 and 1.7 Hz, 1H), 7.34
(d, J = 8.0 Hz, 2H), 7.26 (s, 1H), 7.12 (d, J = 7.9 Hz, 2H), 3.75 (s, 2H), 3.59 (s, 3H), 2.35 (s, 3H);
13C{1H} NMR (75 MHz, CDCl3): δ 161.8 (C), 138.9 (C), 138.5 (C), 137.4 (C), 132.4 (CH), 131.6
(2xCH), 130.2 (CH), 129.2 (2xCH), 127.5 (CH), 124.4 (C), 122.1 (CH), 120.0 (C), 110.3 (C), 84.5
(C), 84.4 (C), 37.2 (CH3), 21.6 (CH3), 20.4 (CH2); IR (neat) νmax 3034, 2910, 1657, 1631, 1596,
864, 812, 773, 732 cm-1; MS (ESI) m/z 322.1002 [M+H]+; HMRS (ESI-TOF): [M+H]+ calc. for
C20H17ClNO: 322.0999; found: 322.1002.
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4-(3-(3,4-dimethoxyphenyl)prop-2-yn-1-yl)-2-methyl-6-(trifluoromethyl)isoquinolin-1(2H)-
one 3eC: Compound 3eC was prepared according to the general procedure D: [acid 1C (0.41
mmol, 1 eq.), allenamide 2e (0.615 mmol, 1.5 eq.), Pd(OAc)2 (0.041 mmol, 0.1 eq.),
PCy3•HBF4 (0.082 mmol, 0.2 eq.), Cs2CO3 (0.82 mmol, 2 eq.), PivOH (0.123 mmol, 0.3 eq.)
1,4-dioxane (1.5 mL)]. The crude product was purified by flash chromatography (EtOAc/PE
55:45) to afford the product 3eC as a yellow solid (129 mg) in 78% yield. mp = 157 °C
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(Et2O/PE); H NMR (300 MHz, CDCl3): δ 8.59 (d, J = 8.4 Hz, 1H), 8.03 (s, 1H), 7.71 (d, J = 8.4
Hz, 1H), 7.28 (s, 1H), 7.01 (dd, J = 8.3 and 1.6 Hz, 1H), 6.91 (d, J = 1.4 Hz, 1H), 6.78 (d, J = 8.3
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Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.82 (s, 2H), 3.62 (s, 3H); C{1H} NMR (75 MHz, CDCl3): δ
161.6 (C), 149.5 (C), 148.7 (C), 136.1 (C), 133.7 (q, J = 32.4 Hz, C), 132.4 (CH), 129.5 (CH),
128.2 (C), 124.9 (CH), 123.9 (q, J = 273.0 Hz, C), 123.0 (q, J = 3.2 Hz, CH), 120.2 (q, J = 4.0 Hz,
CH), 115.1 (C), 114.3 (CH), 111.1 (CH, C), 84.3 (C), 83.6 (C), 56.0 (CH3), 55.9 (CH3), 37.3 (CH3),
20.5 (CH2); 19F NMR (282 MHz, CDCl3) δ -62.77; IR (neat) νmax 3060, 2938, 2838, 1658, 1635,
1513, 1311, 1165, 1121, 1075, 694 cm-1; MS (ESI) m/z 402.1313 [M+H]+; HMRS (ESI-TOF):
[M+H]+ calc. for C22H19F3NO3: 402.1317; found: 402.1313.
4-(3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)-2,7-dimethylisoquinolin-1(2H)-one
3fL:
Compound 3fL was prepared according to the general procedure D: [acid 1L (0.41 mmol, 1
eq.), allènamide 2f (0.615 mmol, 1.5 eq.), Pd(OAc)2 (0.041 mmol, 0.1 eq.), PCy3•HBF4 (0.082
mmol, 0.2 eq.), Cs2CO3 (0.82 mmol, 2 eq.), PivOH (0.123 mmol, 0.3 eq.) 1,4-dioxane (1.5
mL)]. The crude product was purified by flash chromatography (EtOAc/PE 3:7) to afford the
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product 3efL as a yellow solid (117 mg) in 79% yield. mp = 164 – 165 °C (Et2O/PE); H NMR
(300 MHz, CDCl3): δ 8.31 (s, 1H), 7.65 – 7.48 (m, 8H), 7.44 (t, J = 7.4 Hz, 2H), 7.36 (t, J = 7.2
Hz, 1H), 7.20 (s, 1H), 3.83 (s, 2H), 3.62 (s, 3H), 2.51 (s, 3H); C{1H} NMR (75 MHz, CDCl3): δ
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162.5 (C), 141.0 (C), 140.4 (C), 137.2 (C), 133.8 (C), 133.7 (CH), 132.2 (2xCH), 130.1 (CH),
129.0 (2xCH), 128.1 (CH), 127.8 (CH), 127.1 (4xCH), 126.0 (C), 122.4 (CH), 122.2, (C) 111.1 (C),
86.7 (C), 83.7 (C), 37.2 (CH3), 21.6 (CH3), 20.6 (CH2); IR (neat) νmax 3060, 3027, 2923, 1653,
1629, 1610, 845, 760, 692, 494 cm-1; MS (ESI) m/z 364.1708 [M+H]+; HMRS (ESI-TOF): [M+H]+
calc. for C26H22NO: 364.1701; found: 364.1708.
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2,6,7-trimethyl-4-(3-(triisopropylsilyl)prop-2-yn-1-yl)isoquinolin-1(2H)-one 3gI: Compound
3gI was prepared according to the general procedure D: [acid 1I (0.41 mmol, 1 eq.),
allenamide 2g (0.615 mmol, 1.5 eq.), Pd(OAc)2 (0.041 mmol, 0.1 eq.), PCy3•HBF4 (0.082
mmol, 0.2 eq.), Cs2CO3 (0.82 mmol, 2 eq.), PivOH (0.123 mmol, 0.3 eq.) 1,4-dioxane (1.5
mL)]. The crude product was purified by flash chromatography (EtOAc/PE 2:8) to afford the
product 3gI as a white solid (92 mg) in 59% yield. mp = 144 °C (Et2O/PE); 1H NMR (300 MHz,
CDCl3): δ 8.43 (d, J = 7.8 Hz, 1H), 7.42 (d, J = 6.8 Hz, 1H), 7.36 (d, J = 5.0 Hz, 2H), 3.94 (s, 2H),
3.58 (s, 3H), 2.81 (s, 3H), 1.07 (s, 21H); 13C{1H} NMR (75 MHz, CDCl3): δ 136.2 (CH), 135.6 (C),
133.6 (2xC), 132.0 (CH), 127.5 (C), 127.1 (C), 126.7 (CH), 112.0 (C), 105.4 (C), 85.6 (C), 36.8
(2xCH3), 25.3 (CH2), 24.1 (CH3), 18.8 (6xCH3), 11.4 (3xCH); IR (neat) νmax 3347, 2969, 2944,
2865, 2172, 1646, 1621, 1047, 761, 673, 661, 614 cm-1; MS (ESI) m/z 382.2557 [M+H]+;
HMRS (ESI-TOF): [M+H]+ calc. for C24H36NOSi: 382.2556; found: 382.2557.
7-fluoro-2-methyl-4-(3-(triisopropylsilyl)prop-2-yn-1-yl)isoquinolin-1(2H)-one
3cI:
Compound 3cI was prepared according to the general procedure E: [t-BuOK (0.123 mmol,
0.3 eq.), 1,4-dioxane (2 x 0,5 mL) then, PivOH (0.123 mmol, 0.3 eq.), and then acid 1I (0.41
mmol, 1 eq.), allenamide 2c (0.615 mmol, 1.5 eq.), Pd(OAc)2 (0.041 mmol, 0.1 eq.),
PCy3•HBF4 (0.082 mmol, 0.2 eq.), Cs2CO3 (0.82 mmol, 2 eq.), 1,4-dioxane (1.5 mL)]. The
crude product was purified by flash chromatography (EtOAc/PE 15:85) to afford the product
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3cI as a brown solid (124 mg) in 81% yield. mp = 143 - 145 °C (Et2O/PE); H NMR (300 MHz,
CDCl3): δ 8.09 (dd, J = 9.4 and 2.8 Hz, 1H), 7.61 (dd, J = 8.9 and 5.0 Hz, 1H), 7.38 (td, J = 8.5
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and 2.8 Hz, 1H), 7.24 (s, 1H), 3.65 (s, 2H), 3.58 (s, 3H), 1.07 (s, 21H); C{1H} NMR (75 MHz,
CDCl3): δ 161.6 (d, J = 3.5 Hz, C), 161.5 (d, J = 247.7 Hz, C), 132.5 (d, J = 2.2 Hz, C), 130.2 (d, J
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= 2.5 Hz, CH), 127.5 (d, J = 7.9 Hz, C), 124.8 (d, J = 7.9 Hz, CH), 120.7 (d, J = 23.5 Hz, CH),
113.4 (d, J = 22.8 Hz, CH), 110.9 (C), 103.6 (C), 85.1 (C), 37.1 (3xCH), 21.0 (CH2), 18.7 (6xCH3),
11.3 (CH3); 19F NMR (282 MHz, CDCl3) δ -112.99 (td, J = 8.7, 5.0 Hz); IR (neat) νmax 2943, 2865,
2171, 1657, 1629, 1612, 848, 664 cm-1; MS (ESI) m/z 372.2166 [M+H]+; HMRS (ESI-TOF):
[M+H]+ calc. for C22H31NOFSi: 372.2159; found: 372.2166.
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tert-butyl 3-(3-phenylprop-2-yn-1-yl)-1H-indole-1-carboxylate 7aA: Compound 7aA was
prepared according to the general procedure D: [acid 1A (0.41 mmol, 1 eq.), allenamide 6a
(0.615 mmol, 1.5 eq.), Pd(OAc)2 (0.041 mmol, 0.1 eq.), PCy3•HBF4 (0.082 mmol, 0.2 eq.),
Cs2CO3 (0.82 mmol, 2 eq.), PivOH (0.123 mmol, 0.3 eq.) 1,4-dioxane (1.5 mL)]. The crude
product was purified by flash chromatography (CH2Cl2/PE 8:92) to afford the product 7aA as
a pale yellow solid (106 mg) in 78% yield. Exhibited spectra data identical to previous
reports.27 1H NMR (300 MHz, CDCl3): δ 8.06 (d, J = 7.0 Hz, 1H), 7.55 (d, J = 8.1 Hz, 2H), 7.36
(dd, J = 6.5 and 2.9 Hz, 2H), 7.29 – 7.11 (m, 5H), 3.76 (s, 2H), 1.59 (s, 9H).
tert-butyl 3-(3-(pyridin-3-yl)prop-2-yn-1-yl)-1H-indole-1-carboxylate 7aJ: Compound 7aJ
was prepared according to the general procedure D: [acid 1J (0.41 mmol, 1 eq.), allenamide
6a (0.615 mmol, 1.5 eq.), Pd(OAc)2 (0.041 mmol, 0.1 eq.), PCy3•HBF4 (0.082 mmol, 0.2 eq.),
Cs2CO3 (0.82 mmol, 2 eq.), PivOH (0.123 mmol, 0.3 eq.) 1,4-dioxane (1.5 mL)]. The crude
product was purified by flash chromatography (EtOAc/PE 3:7) to afford the product 7aJ as a
brown viscous oil (77 mg) in 56% yield. 1H NMR (300 MHz, CDCl3): δ 8.69 (s, 1H), 8.51 (d, J =
4.7 Hz, 1H), 8.17 (d, J = 8.2 Hz, 1H), 7.73 (dt, J = 8.0 and 1.8 Hz, 1H), 7.66 (s, 0H), 7.63 (s, 2H),
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7.40 – 7.19 (m, 3H), 3.88 (d, J = 1.3 Hz, 2H), 1.69 (s, 9H); C{1H} NMR (75 MHz, CDCl3): δ
152.2 (CH), 149.8 (C), 148.1 (CH), 138.8 (CH), 135.7 (C), 129.7 (C), 124.7 (CH), 123.5 (CH),
123.1 (CH), 122.7 (CH), 120.8 (C), 118.9 (CH), 115.7 (C), 115.5 (CH), 90.4 (C), 83.8 (C), 78.6
(C), 28.3 (3xCH3), 16.3 (CH2); IR (neat) νmax 2980, 1732, 1637, 1455, 1256, 1156, 1074, 744
cm-1; MS (ESI) m/z 333.1611 [M+H]+; HMRS (ESI-TOF): [M+H]+ calc. for C21H21N2O2: 333.1603;
found: 333.1611.
tert-butyl 3-(3-(4-methoxyphenyl)prop-2-yn-1-yl)-1H-indole-1-carboxylate 7aM: Compound
7aM was prepared according to the general procedure D: [acid 1M (0.41 mmol, 1 eq.),
allenamide 6a (0.615 mmol, 1.5 eq.), Pd(OAc)2 (0.041 mmol, 0.1 eq.), PCy3•HBF4 (0.082
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mmol, 0.2 eq.), Cs2CO3 (0.82 mmol, 2 eq.), PivOH (0.123 mmol, 0.3 eq.) 1,4-dioxane (1.5
mL)]. The crude product was purified by flash chromatography (CH2Cl2/PE 15:85) to afford
the product 7aM as a yellow oil (115 mg) in 78% yield. 1H NMR (300 MHz, CDCl3): δ 8.14 (d, J
= 7.8 Hz, 1H), 7.69 – 7.58 (m, 2H), 7.38 (d, J = 8.6 Hz, 2H), 7.35 – 7.21 (m, 2H), 6.83 (d, J = 8.7
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Hz, 2H), 3.83 (s, 2H), 3.80 (s, 3H), 1.67 (s, 9H); C{1H} NMR (75 MHz, CDCl3): δ 159.4 (C),
149.9 (C), 135.8 (C), 133.1 (2xCH), 129.9 (C), 124.6 (CH), 123.5 (CH), 122.6 (CH), 119.1 (CH),
116.6 (C), 115.8 (C), 115.4 (CH), 114.0 (2xCH), 85.0 (C), 83.7 (C), 81.8 (C), 55.4 (CH3), 28.4
(3xCH3), 16.3 (CH2); IR (neat) νmax 2925, 2854, 1727, 1376, 1242, 1156, 1076, 829, 744 cm-1;
MS (ESI) m/z 362.1759 [M+H]+; HMRS (ESI-TOF): [M+H]+ calc. for C23H24NO3: 362.1756;
found: 362.1759.
tert-butyl 3-(3-([1,1'-biphenyl]-4-yl)prop-2-yn-1-yl)-5-chloro-1H-indole-1-carboxylate 7bL:
Compound 7bL was prepared according to the general procedure D: [acid 1L (0.41 mmol, 1
eq.), allènamide 6b (0.615 mmol, 1.5 eq.), Pd(OAc)2 (0.041 mmol, 0.1 eq.), PCy3•HBF4 (0.082
mmol, 0.2 eq.), Cs2CO3 (0.82 mmol, 2 eq.), PivOH (0.123 mmol, 0.3 eq.) 1,4-dioxane (1.5
mL)]. The crude product was purified by flash chromatography (CH2Cl2/PE 15:85) to afford
1
the product 7bL as a yellow viscous oil (134 mg) in 80% yield. H NMR (300 MHz, CDCl3): δ
8.09 (d, J = 8.2 Hz, 1H), 7.68 – 7.50 (m, 8H), 7.45 (t, J = 7.5 Hz, 2H), 7.37 (d, J = 7.2 Hz, 1H),
7.31 (dd, J = 8.8, 1.8 Hz, 1H), 3.83 (s, 2H), 1.68 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3): δ 149.5
(C), 140.8 (C), 140.5 (C), 134.2 (C), 132.2 (2xCH), 131.0 (C), 129.0 (2xCH), 128.4 (C), 127.7
(CH), 127.1 (2xCH), 127.1 (2xCH), 124.8 (CH), 122.4 (C), 118.8 (CH), 116.5 (CH), 115.8 (C),
86.8 (C), 84.2 (C), 82.2 (C), 28.3 (3xCH3), 16.3 (CH2); IR (neat) νmax 2978, 1732, 1370, 1152,
1062, 762 cm-1; MS (ESI) m/z 442.1573 [M+H]+; HMRS (ESI-TOF): [M+H]+ calc. for
C28H25ClNO2: 442.1574; found: 442.1573.
tert-butyl
5-chloro-3-(3-(3,4-dimethoxyphenyl)prop-2-yn-1-yl)-1H-indole-1-carboxylate
7bC: Compound 7bC was prepared according to the general procedure D: [acid 1C (0.41
mmol, 1 eq.), allenamide 6b (0.615 mmol, 1.5 eq.), Pd(OAc)2 (0.041 mmol, 0.1 eq.),
PCy3•HBF4 (0.082 mmol, 0.2 eq.), Cs2CO3 (0.82 mmol, 2 eq.), PivOH (0.123 mmol, 0.3 eq.)
1,4-dioxane (1.5 mL)]. The crude product was purified by flash chromatography (CH2Cl2/PE
35:65) to afford the product 7bC as a brown viscous oil (107 mg) in 61% yield.1H NMR (300
MHz, CDCl3): δ 8.05 (d, J = 8.5 Hz, 1H), 7.65 – 7.57 (m, 2H), 7.32 – 7.23 (m, 1H), 7.04 (dd, J =
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8.3 and 1.5 Hz, 1H), 6.95 (d, J = 1.3 Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 3.87 (s, 6H), 3.78 (s, 2H),
1.66 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3): 149.4 (C), 149.3 (C), 148.6 (C), 134.2 (C), 131.0 (C),
128.3 (C), 125.0 (CH), 124.7 (CH), 118.8 (CH), 116.4 (CH), 115.9 (C), 115.7 (C), 114.4 (C), 110.9
(CH), 84.4 (C), 84.1 (C), 82.2 (C), 55.9 (2xCH3), 53.5 (CH), 28.2 (3xCH3), 16.2 (CH2); IR (neat)
νmax 2933, 1731, 1512, 1369, 1151, 848 cm-1; MS (ESI) m/z 426.1470 [M+H]+; HMRS (ESI-
TOF): [M+H]+ calc. for C24H25ClNO4: 426.1472; found: 426.1470.
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tert-butyl 3-(3-(4-chlorophenyl)prop-2-yn-1-yl)-5-methyl-1H-indole-1-carboxylate 7cE:
Compound 7cE was prepared according to the general procedure D [acid 1E (0.41 mmol, 1
eq.), allènamide 6c (0.615 mmol, 1.5 eq.), Pd(OAc)2 (0.041 mmol, 0.1 eq.), PCy3•HBF4 (0.082
mmol, 0.2 eq.), Cs2CO3 (0.82 mmol, 2 eq.), PivOH (0.123 mmol, 0.3 eq.) 1,4-dioxane (1.5
mL)]. The crude product was purified by flash chromatography (CH2Cl2/PE 8:92) to afford the
product 7cE as a yellow oil (98 mg) in 92% yield. 1H NMR (300 MHz, CDCl3): δ 8.31 (d, J = 6.8
Hz, 1H), 7.88 (s, 1H), 7.72 (dd, J = 8.5 and 5.3 Hz, 3H), 7.47 (d, J = 8.4 Hz, 1H), 7.30 (t, J = 8.7
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Hz, 2H), 4.10 (s, 2H), 2.78 (s, 3H), 1.97 (s, 9H); C{1H} NMR (75 MHz, CDCl3): δ 164.0 (C),
160.7 (C), 149.9 (C), 134.0 (C), 133.6 (CH), 133.5 (CH), 132.1 (C), 130.0 (C), 126.0 (CH), 123.6
(CH), 119.8 (C), 119.7 (C), 118.9 (CH), 116.0 (C), 115.7 (CH), 115.4 (CH), 115.1 (CH), 86.4 (C),
83.6 (C), 80.9 (C), 29.9 (C), 28.3 (3xCH3), 21.6 (CH3), 16.2 (CH2); IR (neat) νmax 3676, 2974,
2923, 1727, 1370, 1232, 1149, 1076 cm-1; MS (ESI) m/z 380.1421 [M+H]+; HMRS (ESI-TOF):
[M+H]+ calc. for C23H23ClNO2: 380.1417; found: 380.1421.
tert-butyl 5-methyl-3-(3-(triisopropylsilyl)prop-2-yn-1-yl)-1H-indole-1-carboxylate 7cI:
Compound 7cI was prepared according to the general procedure D: [acid 1I (0.41 mmol, 1
eq.), allenamide 6c (0.615 mmol, 1.5 eq.), Pd(OAc)2 (0.041 mmol, 0.1 eq.), PCy3•HBF4 (0.082
mmol, 0.2 eq.), Cs2CO3 (0.82 mmol, 2 eq.), PivOH (0.123 mmol, 0.3 eq.) 1,4-dioxane (1.5
mL)]. The crude product was purified by flash chromatography (CH2Cl2/PE 2:98) to afford the
product 7cI as a yellow viscous oil (128 mg) in 73% yield. 1H NMR (300 MHz, CDCl3): δ 8.03 (s,
1H), 7.53 (s, 1H), 7.34 (s, 1H), 7.15 (d, J = 8.3 Hz, 1H), 3.67 (s, 2H), 2.45 (s, 3H), 1.66 (s, 9H),
1.12 (d, J = 2.4 Hz, 21H); 13C{1H} NMR (75 MHz, CDCl3): δ 149.8 (C), 132.0 (C), 129.9 (C), 125.9
(CH), 123.5 (CH), 118.9 (CH), 116.2 (C), 115.0 (C), 104.8 (CH), 83.2 (C), 82.4 (C), 28.4 (3xCH3),
21.5 (CH3), 18.8 (6xCH3), 16.9 (CH2), 11.4 (3xCH); IR (neat) νmax 2942, 2865, 1736, 1369, 1249,
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1151, 676 cm-1; MS (ESI) m/z 426.2830 [M+H]+; HMRS (ESI-TOF): [M+H]+ calc. for
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C26H40NO2Si: 426.2828; found: 426.2830.
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Supporting Information
Supporting Information
Copies of 1H and 13C NMR spectra of all new compounds 3 and 7.
AUTHOR INFORMATION
ORCID
Christophe Hoarau: 0000-0001-9668-99706
Cédric Schneider: 0000-0002-5128-5646
Isabelle Gillaizeau: 0000-0002-7726-3592
ACKNOWLEDGEMENT
This work has been partially supported by INSA Rouen, Rouen University, CNRS, EFRD, European
INTERREG IV A France (Channel) and Labex SynOrg (ANR-11-LABX-0029). We also thank the CRIHAN
for software optimization and technical support.
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Domino Reactions − Diverse Oligocyclizations of Acyclic 2-Bromoenynes and 2-
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Grigg, R.; Sridharan, V.; Xu, L.-H., Palladium-Catalysed Cyclisation–Amination of
Allenes-Effect of Base on Regioselectivity of Formation of Allylic Amines. J. Chem. Soc.,
Chem. commun. 1995, 1903-1904. (b) Grigg, R.; Loganathan, V.; Sridharan, V.; Stevenson, P.;
Sukirthalingam, S.; Worakun, T., Palladium Catalysed Tandem Cyclisation-Anion Capture
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For complete details concerning the screening of solvents, bases, palladium, ligands
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Allenamides were prepared by the base-induced isomerization using a catalytic
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