Valorization of CO2: Preparation of 2-Oxazolidinones by Metal-Ligand Cooperative Catalysis with SCS Indenediide Pd Complexes

Article abstract of DOI:10.1021/acscatal.7b00209

The capture and utilization of CO₂ to prepare high-value compounds is very attractive chemically and highly desirable socially. Indenediide-based Pd SCS pincer complexes are shown here to promote the carboxylative cyclization of propargylamines

Full text of DOI:10.1021/acscatal.7b00209

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Article
Valorization of CO2: Preparation of 2-Oxazolidinones by Metal /
Ligand Cooperative Catalysis with SCS Indenediide Pd Complexes
Paul Brunel, Julien Monot, Christos E. Kefalidis, Laurent Maron, Blanca Martin-Vaca, and Didier Bourissou
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b00209 • Publication Date (Web): 07 Mar 2017
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Valorization of CO2: Preparation of 2-
Oxazolidinones by Metal / Ligand Cooperative
Catalysis with SCS Indenediide Pd Complexes
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Paul Brunel,a Julien Monot,a Christos E. Kefalidis,b Laurent Maron,b Blanca Martin-Vaca,*a
and Didier Bourissou*a
a Université de Toulouse, UPS, LHFA, UMR 5069 CNRS, 118 route de Narbonne, F-31062
Toulouse, France.
b Universite de Toulouse, INSA, UPS, LPCNO, UMR 5215 CNRS, 135 avenue de Rangueil,
́
31400 Toulouse, France.
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ABSTRACT.
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The capture and utilization of CO2 to prepare high-value compounds is very attractive chemically
and highly desirable socially. Indenediide-based Pd SCS pincer complexes are shown here to
promote the carboxylative cyclization of propargylamines leading to 2-oxazolidinones under mild
conditions (0.5-1 bar of CO2, DMSO, 40-80°C, 1-5 mol% Pd loading). The indenediide Pd
complex is competitive with known catalysts. It proved successful for a wide range of
propargylamines, including hitherto challenging substrates such as secondary propargylamines
bearing tertiary alkyl groups at nitrogen, primary propargylamines and propargylanilines.
Thorough experimental (NMR) and computational (DFT) investigations were undertaken to gain
mechanistic insights. Accordingly, (i) the resting state of the catalytic cycle is a Pd DMSO
complex, (ii) the indenediide backbone and Pd center act in concert to activate the carbamic acid
intermediate and promote its cyclization, (iii) proton shuttling is essential to lower the activation
barriers of the initial amine carboxylation as well as of the proton transfers between the ligand
backbone and the organic fragments at Pd.
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Keywords: CO2 functionalization; palladium; metal-ligand cooperative catalysis; proton shuttling;
catalytic cycle
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Introduction
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Over the last decades, the valorization of CO2 as an abundant and non-toxic C1 feedstock has
garnered increasing interest from chemists and the whole scientific community.1 The chemical
transformation of CO2 has the advantage of creating added-value from a raw material. It is very
complementary to sequestration2 in order to reduce the deleterious greenhouse effect of ever-
increasing CO2 emission. To chemically transform CO2, several approaches involving reduction
and/or functionalization have been envisioned and undertaken. Reduction into formic acid or
methanol (as a mean to store H2) are undoubtedly the most intensively investigated CO2
transformations. A number of organic and organometallic catalysts have been reported to
efficiently mediate these reductions.3 In addition, more and more studies have been performed
over the last decade on the reductive functionalization of CO2 leading the formation of new C–N,
C–O, C–C bonds. Very promising results have been obtained along this line too.4 Great interest
has also been devoted to the use of CO2 as raw material to prepare functional molecules (and
polymers) in which the CO2 moiety is not reduced,5 such as carbonates, carbamates or urethanes
(and polymers thereof). Among them, 2-oxazolidinones (fixe-membered cyclic carbamates) stand
as prominent compounds with a broad variety of applications ranging from organic synthesis
(chiral auxiliaries,6 synthons7), agrochemistry and pharmaceutical chemistry,8 as well as polymer
science.9 Different strategies have been developed for the preparation of 2-oxazolidinones using
CO2 as a C1 building block and aziridines,5b,10 haloalkylamines11 or propargylamines5,10 as
nucleophilic reaction partners. Due to their ready availability and wide structural diversity,
propargylamines are particularly appealing starting materials and their carboxylative cyclization
leading to alkylidene-oxazolidinones (whose exocyclic C=C double bond can be subsequently
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reduced or further derivatized) is a very attractive transformation combining CO2 capture and
utilization.
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The search for efficient catalysts started with the seminal discovery of Mitsudo and Watanabe
in 1987 using [Ru(COD)(COT)] (COD = 1,5-cyclooctadiene, COT = 1,3,5-cyclooctatriene) /
PPh3.12 However, this catalytic system and those reported in the 1990’s operate under relatively
harsh conditions (~ 100°C, ≥ 10 bar of CO2) and a strong base is often needed.13 Over the last
decade, the search for efficient catalytic systems working under milder conditions, in particular
low pressure of CO2, has stimulated much interest and significant progress has been achieved.
Most noticeable contributions (Figure 1a) are those using silver salts (AgNO3, AgOAc) in the
presence of an excess of DBU (1,8-diazabicycloundec-7-ene), as initially reported by Yamada in
2009 (these are among the most, if not the most, versatile catalysts known to date for this
transformation),14,15 and the NHC gold(I) complex (IPr)AuCl [IPr = 1,3-bis(2,6-
diisopropylphenyl)-imidazol-2-ylidene] described by Ikariya in 201316 (which performs
particularly well with N-alkyl propargylamines bearing an internal alkyl-substituted alkyne).17 In
addition, C. Nevado reported in 2016 an efficient Pd-catalyzed synthesis of oxazolidinones,
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2
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combining the carboxylative cyclization of propargylamines with Csp -Csp cross-coupling (Figure
1b).18 This one-pot two-step transformation gives access to highly-substituted alkylidene-
oxazolidinones in good to excellent yields. Thanks to all these studies, the efficiency and operating
conditions of the title transformation have been significantly improved, but there are still issues to
overcome in order to extend its scope and strengthen its synthetic interest. In particular, the
following subclasses of substrates are still challenging: (i) secondary propargylamines featuring
tertiary alkyl groups at the nitrogen atom, (ii) primary propargylamines (their nitrogen atom is less
nucleophilic and the resulting N-H oxazolidinone are less stable),19 (iii) propargylanilines (their
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nitrogen atom is also less nucleophilic and the corresponding N-aryl oxazolidinones are usually
prepared in two steps) and (iv) homopropargylamines whose carboxylative cyclization would
afford direct access to six-membered cyclic carbamates, namely 1,3-oxazin-2-ones.
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O
R1
a a
t l
s
t
C
y
N
O
a
( )
R3
R2
R2
H
N
R4
+
CO2
ar
R1
O
R3
R4
1 b
R1
-
r
A I
N
O
b
( )
Pd
l
dppf
.
C 2
[
]
)
R3
(
R2
R4
ca
t
(
)
.
r
A
t
a
N
u
B
e
1 5
q
)
O
(
Figure 1. Schematic representation of the catalytic carboxylative cyclization of propargylamines;
comparison of the efficiency and scope of the key metal complexes recently shown to promote this
transformation under mild conditions, including the indenediide SCS Pd complex studied in this
work.
Over the last few years, we have developed new SCS (and NCN) tridentate ligands deriving
from indene.20 The corresponding Pd and Pt complexes were shown to efficiently promote the
cycloisomerization of alkynoic acids and N-tosyl akynylamides (Chart 1).21,22 Even very
challenging substrates were successfully transformed and a variety of alkylidene-lactones and
lactams, including 7-membered rings were thereby obtained in good yields and with high
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selectivities.21 Detailed mechanistic investigations performed on alkynoic acids revealed the active
participation of the electron-rich indenediide moiety which temporarily fixes a proton of the
carboxylic acids, while a second molecule of substrate acts as a proton shuttle.23
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PR2
R2P
R
S
S
]
%
Pd Pt
/
O
[
-
XH
X
R
O
mo
l
X
1 5
O
n
,
=
s
X
NT
-
O
n
R
n
=
n
1 3
x
e o
e
n
o
d
Chart 1. Cycloisomerization of alkynoic acids and N-tosylalkynylamides catalyzed by
indenediide-based palladium or platinum pincer complexes.
Taking into account that the carboxylative cyclization of propargylamines involves as key
intermediates carbamic acids, whose structure is reminiscent to that of alkynoic acids, we became
interested in exploring the behavior of our indenediide-based Pd and Pt complexes in this
transformation. We wondered about the compatibility of these pincer complexes with CO2 fixation
and their ability to catalyze the formation of alkylidene-oxazolidinones. As reported hereafter,
indenediide-based Pd complexes were indeed found to promote efficiently the carboxylative
cyclization of propargylamines under mild conditions. The scope of the transformation has been
enlarged to include secondary propargylamines with bulky alkyl and electron-rich aryl substituents
at N, as well as primary propargylamines. Mechanistic studies substantiating the resting state of
the catalytic cycle, the contribution of the indenediide backbone (metal-ligand cooperativity) and
the key role of proton shuttling are also reported.
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Results and Discussion
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Catalytic evaluation of SCS indenediide pincer complexes in the carboxylative cyclization of
propargylamines and homopropargylamines.
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The catalytic activity of indenediide-based SCS pincer complexes was first evaluated in the
carboxylative cyclization of N-methylpropargylamine (1a) as benchmark reaction (Table 1). The
reaction conditions were optimized and the activities of the four complexes (I-IV) were compared.
Initial tests were carried out with the dimeric Pd complex I, which performed best in the
cycloisomerization of alkynoic acids and alkynyl amides.21 The influence of the solvent was
investigated first.24 The catalytic runs were directly performed in deuterated solvents and
1
monitored by H NMR spectroscopy, using 5 mol% loading of Pd, working at 50°C and
atmospheric pressure of CO2. No reaction occurred in acetone (entry 1) and only low conversions
of 1a (7-19%, entries 2-6) were observed in chloroform, dimethylformamide, tetrahydrofurane or
methanol. By far, the best results were obtained in dimethylsulfoxide (DMSO), full conversion of
1a being reached within 20 minutes (entry 7). Thus the solvent has a marked influence on the
reaction, and it is clearly not simply the solubility of carbon dioxide which governs the efficiency
of the transformation since CO2 is >2 times more soluble in acetone and THF (1.95 and 2.7 mol%,
respectively, at 25°C and 1 atm) than in DMSO (0.9 mol%).25 Such carboxylative cyclizations
typically proceed faster in DMSO, as reported by T. Yamada with Ag+/DBU15 and by C. Nevado
with PdCl2(dppf).18 In stark contrast, T. Ikariya noticed that the gold(I) complex (IPr)AuCl
performs best in methanol, a protic solvent being required in this case to promote the final
protodeauration step.16b The lower conversion we observed in methanol most likely results from
the low solubility of complex I in this solvent. Increasing the reaction temperature substantially
speeded up the transformation, allowing the catalyst loading to be reduced to 1 mol% Pd in DMSO
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(Figure S1).24 Accordingly, full conversion of 1a could be achieved within only ten minutes at
80°C (entry 8). Conversely, working at higher CO2 pressure (2 bar) did not increase significantly
the reaction rate,24 confirming that CO2 solubility is not a limiting factor. Thus the reaction can be
efficiently and conveniently performed at low pressure of CO2 (0.5-1 bar).26 The impact of the
catalyst structure was then evaluated in DMSO at 70°C and 1 bar of CO2 using 1 mol% Pd. The
chloropalladate II showed similar activity as the neutral dimer I (entries 9 and 10), indicating that
the chloride co-ligand at Pd and the ammonium counter-cation have no noticeable influence. By
contrast, alkylation of the indenediide backbone drastically decreased the catalytic activity. Indeed,
the 1-methylindenyl-based palladium complex III proved to be only poorly active, giving 10% of
conversion after 10 min of reaction (entry 11) vs. 55% with I. This result supports an active role
of the indenediide backbone (see mechanistic discussions below), in line with what we previously
reported for cycloisomerization reactions.21,23 Finally, the Pt complex IV was evaluated and found
to display moderate activity (20% conversion after 10 min, entry 12). Thus, the Pd complex I
afforded the best results and it was selected for the following catalytic studies.
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Table 1. Reaction conditions and indenediide-based SCS pincer complexes I-IV evaluated in the
benchmark carboxylative cyclization of N-methylpropargylamine 1a.
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O
. -
0 5 5
.
e
M
mo
. -
l
Pd
]
%
[
N
O
e
M
HN
a
r
5 1 b
t h
C
) ( )
CO2 0
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,
,
°
a
1
v n
so e
a
l
t T
2
(
n
u
B
4N
i
i
r
r
P P
2
i
i
P P
i
i
r
r
r
2
r
2
P P
P P
P P
P P
2
2
2
Pd
l
S
S
S
Pt
Pd
S
S
S
S
II
C
Pt
Pd
S
S
S
S
i
i
i
i
r
r
r
r
P P
P P
P P
P P
e
2
2
2
2
M
PPh2
Ph2P
IV
I
Pd
l
S
III
C
Entrya Cat. Solvent
T
mol% Time Conv
(°C)
Pd
(h)
(%)b
1
2
(CD3)2CO 50
5
6
-
I
I
CD3CN
DMF-d7
THF-d8
CDCl3
50
50
50
50
50
5
4.5
4.5
4.5
6
7
3
5
17
19
13
11
99
99
55
53
10
20
I
4
5
I
5c
6
5
I
CD3OD
5
1
I
7
DMSO-d6 50
DMSO-d6 80
DMSO-d6 70
DMSO-d6 70
DMSO-d6 70
DMSO-d6 70
5
0.33
0.16
0.16
0.16
0.16
0.16
I
8
1
I
9
1
I
10
11
12
1
II
III
IV
1
1
(a) All catalytic tests were performed starting from 0.8
mmol of N-methylpropargylamine (1 M solutions), at 1 bar
of CO2 and 5 or 1 mol% Pd loading. (b) Conversions were
determined by 1H NMR.
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The substrate scope of the reaction was then explored using DMSO as solvent (1 M solutions)
and working at 1 mol% Pd loading, 70°C and 1 bar of CO2, as standard conditions (Table 2).
Secondary propargylamines 1a-h were investigated first.24 Clean and quantitative reactions were
observed in all cases (entries 1-8). As expected, the steric demand of the N-substituent strongly
influences the reaction rate. Full conversions were achieved within only 10 min with the N-
methylated and N-benzylated substrates 1a and 1d (entries 1 and 4), whereas 12 h of reaction were
needed for the N-isopropyl substrate 1b (entry 2). Remarkably, complex I was also efficient in
promoting the carboxylative cyclization of the N-tert-butyl substrate 1c. Full conversion could be
achieved after 90 h and the corresponding oxazolidinone was isolated in 88% yield (entry 3). To
the best of our knowledge, this is only the second example of such a transformation with a
propargylamine featuring a tertiary alkyl group at nitrogen. The other one was reported recently
by C. Nevado with PdCl2(dppf)18 but this carboxylative cyclization / cross-coupling reaction
seems to be more sensitive to steric hindrance since only 38 % yield was obtained after heating for
3 days. The substitution of the alkyne, terminal or internal, was then studied and it proved to also
have a clear impact on the reaction rate. Still, very efficient conversions could be achieved in all
cases. Terminal alkynes 1a,b,d were converted more rapidly than their substituted counterparts
1e-h (entries 5-8). At 70°C, reaction times were typically in the range of 12 hours for terminal
alkynes vs. 1-3 days for internal alkynes. Note also that complex I converted the Ph- and Me-
substituted alkynes 1g,h with similar rates (entries 7 and 8).27 But the nature of the alkyne
substituent, aryl or alkyl, has an impact on the regioselectivity of the cyclization. The phenyl-
substituted substrates 1e-1g underwent fully selective 5-exo cyclization, whatever the alkyl group
at nitrogen (entries 5-7), while some 6-endo cyclization was observed with the methyl-substituted
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alkyne 1h (entry 8). Indeed, a 8.25/1 mixture of 5-exo/6-endo oxazolidinones was obtained in this
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case, similarly to what was observed by Yoshida with Ag+/DBU.15c
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Table 2. Substrate scope of the carboxylative cyclization of propargyl and homo-propargylamines
with I.
a
a
º
º
C
b
b
n r
E t y
u s ra e
b t
ro uc
d
onv
C
n r
E t y
u s ra e
b t
ro uc
d
onv
C
t
P
t
T
t h
( )
t
P
t
T
t h
( )
S
C
)
%
S
%
( )
(
(
)
(
)
O
O
,
n
e
f
B
e
>
9d
M
40
144
99 36
(
)
.
N
O
N
O
n
>
1
2
80
70
B
0 16
N
99 90
(
)
e
H
HN
M
a
a
2
1
1i
2i
O
N
O
i
n
r
B
,
P
e
10d
7 f
)
>
>
99 3
(
O
12
90
99 91
(
40
40
48
N
O
)
n
B
i
N
H
r
HN
HN
HN
P
1b
1
j
2b
2
j
n
B
O
H
N
Ph
N
n
B
t
u
ePh
1k
B
g
>
99
>
11d,
1
7
0
3
N
99 88
( )
O
t
u
B
4k
c
1
c
2
Ph
O
Ph
n
.
B
>
>
7
4
1
60
99 95
(
4
5
6
80
0 16
12
0
0
0
N
99 83
(
)
O
)
N
B
n
n
B
B
N
n
1d
H
4l
PMP
2d
1l
O
O
e
M
c
13e
>
>
Ph
N
O
99 74
(
7
0
2
99 98
)
33
36
0
PMP
)
N
(
O
e
M
N
HN
m
1
e
1
m
2
H
e
e
2
Ph
Ph
Ph
=
O
O
PMP p M
6H4
O C
)
O
(
i
,
r
c
)
P
e
Ph
14d
O
O
>
7
0
99 85
HN
90
60
>
4
(
N
99 8
5
( )
O
i
r
HN
P
NH2
NH2
n
1
1f
n
2
2f
O
n
B
c
)
Ph
N
>
99 97
15d
HN
O
7
0
7
8
(
>
40
40
6
99 85
(
)
n
HN
HN
B
1g
2g
o
1
o
2
O
O
n
B
B
O
N
O
O
HN
>
d
O
21
99 85
(
e
M
1
6
2h
)
c
e
M
>
99 74
7
0
60
(
)
NH2
n
B
1p
1h
.
n
exo en o
d
8 25/1
/
N
2p
e
M
3h
(a) General conditions: the catalytic runs were performed starting from 0.8 mmol of the N-
propargyl amine (1 M solutions), at 1 bar of CO2 and 1 mol% Pd loading. (b) Conversions were
1
determined by H NMR using 1,3,5-trimethoxybenzene as internal standard. Isolated yields are
given in brackets. (c) Full Z stereoselectivity was attributed according to literature data, see Supp.
Info. (d) 0.1 M solution of the propargyl amine. (e) 5 mol% Pd loading. (f) Spectroscopic yield.
Compound 2i was isolated in 30% yield. (g) Low stability of the product prevented isolation.
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The good results obtained with secondary propargyl amines prompted us to assess the ability of
I to catalyze the carboxylative cyclization of more challenging substrates such as
homopropargylamines (leading to oxazinones), propargylanilines and primary propargylamines.
The homopropargylamine 1i was prepared24 and reacted with CO2 in the presence of I using the
same conditions as for propargylamines (DMSO, 1 M, 70°C, 1 bar of CO2, 1 mol% Pd loading).
Complete conversion of 1i was observed after a few hours of reaction but 1H NMR spectroscopy
indicated the formation of a complex mixture of compounds containing only a small amount of
carboxylative cyclization product 2i. Working under milder conditions (40°C, 0.1 M) and
increasing the catalytic loading to 5 mol% Pd allowed to decrease the proportion of secondary
products and the desired oxazinone 2i could be thereby obtained in 30% isolated yield.28 Seeking
to favor the cyclization process by Thorpe-Ingold effect, the propargylamine 1j featuring a methyl
group in the position α to nitrogen was then synthesized24 and subjected to the carboxylative
cyclization (entry 10). Unfortunately, only a minor improvement was observed and the
corresponding oxazinone 2j was obtained again in modest yield (37%). With the aim to gain more
insight into the undesirable processes competing with carboxylative cyclization, the
propargylamines 1a and 1e were heated for 48 h in the presence of the Pd complex I (40°C, 0.1
M, 5 mol% of Pd) but in the absence of CO2. While the internal alkyne 1e remained unchanged,
the terminal alkyne 1a was converted into a mixture of unidentified products. This observation
suggests that side-reactions are more likely to occur with substrates featuring terminal alkynes,
spurring us to prepare and test substrate 1k, an homo-propargylamine with an internal (phenyl-
substituted) alkyne moiety. As hoped for, a clean cyclization reaction occurred with 1k (entry 11)
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but H NMR and MS analyses revealed that CO2 was not incorporated. In fact, 5-endo cyclo-
hydroamination leading to the corresponding dehydro-pyrrole 4k was favored over the
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carboxylative cyclization. An attempt was made to fully carboxylate the amine of 1k before
addition of the catalyst, but the outcome was the same, no carboxylation could be observed. Cyclo-
hydroamination was also observed with substrate 1l featuring an o-phenylene spacer between the
amine and the alkyne, and the resulting indole 4l was isolated in 95% yield (entry 12). Note that
carboxylative cyclization of 1l was reported by Yamada using Ag+/DBU as catalyst and working
at 10 atm of CO2.15d,29 The results obtained with homopropargylamines can be summed up as
follows. Complex I allows carboxylative cyclization of 1i,j into alkylidene-oxazinones 2i,j.
Although modest yields were obtained, this is the first time such compounds have been prepared
this way.30 In addition, cyclo-hydroamination (5-endo cyclization) has been identified as a
competitive process to the carboxylative cyclization (6-exo cyclization).
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We then turned our attention to N-propargylanilines, which are extremely scarce substrates for
this type of reaction due to the low nucleophilicity of the nitrogen atom.31 No reaction was
observed from the parent N-propargylaniline HC≡CCH2NHPh, but compound 1m featuring a
para-methoxy group on the phenyl ring led to the desired oxazolidinone 2m in good yield (74%,
entry 13). Thus, complex I enables straightforward and efficient access to oxazolidones featuring
electron-rich aromatic rings at the nitrogen atom, a subclass of oxazolidinones actually known for
their biological activities,8b after suitable derivatization of the alkylidene moiety.
Primary propargylamines are also quite challenging substrates and not surprisingly, their
carboxylative cyclization is much less developed than that of secondary propargylamines. Side-
reactions can arise from the NH2 group and lower yields are typically obtained when compared
with related secondary amines.19,32 Using complex I as catalyst, propargylamines 1n-p (entries 14-
16) led to complex mixtures when the reactions were operated under our standard conditions (1
M, 70°C). As for homopropargylamines, working under milder conditions (0.1 M, 40°C) proved
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highly beneficial. Indeed, NMR monitoring indicated clean and quantitative formation of the
desired N-H oxazolidinones 2n-p which were isolated in 85% yield. Such unsubstituted
oxazolidinones are particularly interesting as direct precursors for N-arylated oxazolidinones.32,33
Accordingly, carboxylative cyclization of primary propargylamines followed by catalytic N-
arylation represents an alternative and complementary route to the carboxylative cyclization of N-
propargylanilines discussed above.
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Mechanistic considerations
The commonly accepted catalytic cycle for these carboxylative cyclizations involves
carboxylation of the propargylamine to form a carbamic acid, activation of the C≡C triple bond by
side-on coordination to the metal center, cyclization by outer-sphere nucleophilic attack of the
carbamic acid and protodemetallation. In order to get more mechanistic insight into the reaction
catalyzed by the Pd complex I, and in particular to shed light on the contribution of the indenediide
ligand, experimental and computational investigations were undertaken.
Reaction monitoring, stoichiometric reactions.
31
The outcome of the Pd complex I was first probed by monitoring some catalytic runs by P
NMR spectroscopy. In all cases, a unique signal at δ 73.9 ppm was observed. This signature
markedly differs from that of the starting complex, which adopts a dimeric structure in solvents
such as CDCl3, giving two 31P NMR signals at δ 77.8 and 71.5 ppm for the inequivalent bridging
and non-bridging P=S groups.21b It is very likely that the signal observed at δ 73.9 ppm in the
catalytic runs results from the dissociation of the dimeric structure of I by coordination of DMSO
to Pd (Scheme 1). This hypothesis was confirmed by the observation of the same unique 31P NMR
signal upon dissolution of complex I in DMSO (in the absence of substrate and CO2). The affinity
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of DMSO for the indenediide Pd fragment was then quantitatively assessed. To do so, increasing
amounts of DMSO were added to a CDCl3 solution of I and the relative proportions of the dimer
and DMSO complexes were measured by 31P NMR (Fig S2). After addition of 2 eq of DMSO per
Pd center, a small peak was observed at δ 73.9 ppm. The two signals associated with the dimeric
structure completely disappeared upon addition of 60 eq of DMSO. The equilibrium constant K
(which corresponds to dimer dissociation and DMSO coordination) was estimated to 2.7x10-2.24
Similar experiments were carried out with the analogous Pt complex IV. In this case, the dimeric
structure was completely splitted upon addition of only 2 eq of DMSO per Pt center (Figure S3),24
indicating a significantly higher affinity of DMSO for Pt than for Pd.34 The strong affinity of the
indenediide Pt fragment for DMSO may contribute to the lower activity of IV in the carboxylative
cyclization of propargylamines, as the reaction requires the substrate to coordinate to the metal
and thus to displace DMSO. We then examined the ability of model alkynes and amines to displace
DMSO from the corresponding Pd adduct. No reaction was observed upon addition of up to 100
eq of phenylacetylene, but a stoichiometric amount of methylbenzylamine was enough to induce
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quantitative transformation, as apparent from P NMR spectroscopy: the signal at δ 73.9 ppm
disappeared and a new signal raised at δ 77.7 ppm.24 The latter signal can be confidently attributed
to the Pd amine complex, by analogy with the related indenediide Pd dicyclohexylamine we
previously reported.20a
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Ph
H
C
C
o reac on
ti
N
i
i
r
r
P P
P P
2
2
i
i
r
r
DM
SO
P P
P P
Pd
S
S
2
2
Pd
S
S
½
Pd
i
S
i
S
r
P P
2
r
P P
n
e
2
B M NH
DM
SO
i
i
r
r
2
P P
P P
Pd
S
S
2
9
N
n
B
I
H
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e
M
Scheme 1. Splitting of the Pd dimer I upon DMSO coordination and subsequent displacement of
DMSO by N-methylbenzylamine.
Based on these studies, we propose that the resting state of the catalytic cycle is the Pd DMSO
complex, whose DMSO molecule is labile enough to be displaced by the propargylamine or the
corresponding carbamic acid so that the C≡C triple bond can be activated and cyclization can take
place. In addition, the very low activity of the related indenyl Pd complex III supports an active
participation of the indenediide moiety (in the activation of the carbamic acid moiety, see the
computational studies below), as in the case of the cycloisomerization reactions we investigated
previously.21,23
To complete the experimental study, we examined the very first stage of the transformation, ie
the carboxylation of propargylamines. Accordingly, compound 1a was found to spontaneously and
quantitatively form the corresponding carbamic acid when reacted with CO2 (1 bar) in DMSO at
1
room temperature. Most diagnostic is the deshielding of the H NMR signal associated with the
NCH2 group (from δ 3.23 ppm in the propargylamine 1a, to δ 4.01 ppm in the corresponding
carbamic acid, see Figure S6).24 Interestingly, the carbamic acid remained unchanged after 3
freeze-pump cycles, but CO2 was slowly released and 1a was recovered upon heating at 80°C
(decarboxylation was complete after ca 12 h).35
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Computational studies.
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DFT calculations were performed at the same level of theory (B3PW91) than the one we used
previously for the cycloisomerization of alkynoic acids.23 However, to account for the striking
effect of DMSO observed experimentally, solvent effects were included by means of the SMD
model (see computational details).24
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The carboxylation of the propargylamine 1a was investigated first. The indenediide Pd complex,
which is not expected to play any role in this step, was not considered and consistently, a low-
energy path was identified for the reaction of 1a with CO2 (Figure 2). It requires the inclusion of
a second molecule of amine 1a, in line with that reported by Yuan and Lin for the carboxylation
of H3CC≡CCH2N(CH3)CO2H in the coordination sphere of gold.36 Interaction of the amine with
CO2 first gives a weak adduct (ad1) which is slightly downhill in energy (by 4.4 kcal.mol-1 in
enthalpy).35,37 Nucleophilic addition of the nitrogen atom to CO2 is then assisted by the second
molecule of amine, which mediates the proton transfer from the attacking nitrogen atom to one of
the oxygen atom of CO2 (TSad12). The formation of the N−CO2 bond (1.58 Å) and the bending of
the CO2 fragment (133.6°) are quite advanced at the transition state. The corresponding activation
barrier is accessible (2.6 kcal.mol-1 in enthalpy from ad1, 22.4 kcal.mol-1 in Gibbs energy from
the initial reactants) and much lower than that computed for the direct carboxylation of 1a without
the assistance of a second amine molecule (∆H≠ 28.7 kcal.mol-1, ∆G≠ 36.5 kcal.mol-1, see Figure
S8).24 This emphasizes the role of proton shuttling, which is optimal in TSad12 (six-membered
cyclic transition state vs. four-membered TS for the direct reaction). Following the intrinsic
reaction coordinate, ad2, an adduct between the carbamic acid and amine molecules is obtained.
Dissociation of the hydrogen bond is relatively demanding in energy (∆H 11.3 kcal.mol-1) but
nevertheless thermodynamically favored (∆G −1.5 kcal.mol-1) due to the large entropic factor
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(formation of two molecules from one). These computational results are consistent with
spontaneous and reversible reaction of the propargylamine 1a with CO2, and therefore corroborate
our experimental observations (formation of the carbamic acid at RT under CO2 atmosphere and
release of CO2 upon heating at 80°C).
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H
C
H
C
H
C
C
C
+
CO2
H
2
C
2
C
H
+
C
2
H
C
2
N
e
M
N
e
M
N
H
e
M
T
Sa
d12
a
H
CO2
.
d1
H
- .
0 0
.
- .
1
8
- .
7
4 4
.
0 0
(
)
3
.
22 4
(
a
H
)
C
d2
.
1
6 9
(
)
7
)
3
(
- .
C
1
8 6
.
e
H
C
M
2
5 2
(
)
H
C
e
C
M
N
HC
N
H
O
C
C
e
M
N
H
C
H
H
C
O
O
C
H2
C
O
H
N
e
M
eac on oor na e
ti
di
R
t
C
Figure 2. Reaction energy profile in enthalpy at room temperature (Gibbs free energy at room
temperature in brackets) for the reaction of propargylamine 1a with CO2 in the presence of a
second propargylamine molecule in DMSO (O in red, N in dark blue).
The intramolecular cyclization of the formed propargylic carbamic acid
HC≡CCH2N(CH3)CO2H was then studied at the same level of theory (B3PW91) including solvent
effects (DMSO, PCM model) and considering the actual indenediide Pd complex (the iPr groups
at P were retained). The corresponding reaction profile is depicted in Figure 3 (for clarity, the
substituents at P are omitted). It is discussed hereafter in parallel and comparison with the reaction
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profiles computed i) by us for the cycloisomerization of alkynoic acids catalyzed by the same
indenediide Pd complex23 and ii) by Yuan and Lin for the carboxylative cyclization of the
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propargylamine H3CC≡CCH2NH(CH3) catalyzed by the NHC gold complex (IPr)AuCl.36,38
A
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second molecule of carbamic acid was included in the calculations to mediate proton transfers and
lower the barriers of the key steps.
T
SB
.
21 8
.
22 4
(
)
T
SA
.
-
n
i t A
8 2
.
.
6 0
.
a
5 7
t
C
(
)
3 2
(
)
.
T
SC
CH
0 0
.
CH
C
- .
0 0
7
3
(
)
C
CH2
N
- .
e
M
0 9
e
O
M
CH2
(
)
e
M
e
C
N
N
O
C
O
M
C
O
O
H
O
-
C
N
O
C
H
2
n
H
i t B
O
S
P
CH2
H
C
C
H
H
S
Pd
P
C
C
H
CH
C
Pd
S
P
-
n
S
i t
-
-
P
C
ac
id
CH2
N
e
M
.
25 0
C
O
S
.
a
.
t
C
7
)
30
O
(
S
H
P
-
H
c c
C
Pd
y
li
ro
uc
t
31 6
- .
O
C
c
S
31 8
O
(
)
H2C
P
N
p
d
e
M
eac on oor na e
ti
di
R
t
C
Figure 3. Reaction energy profile in enthalpy at room temperature (Gibbs free energy at room
temperature in brackets) for the cyclization of the propargylic carbamic acid
HC≡CCH2N(CH3)CO2H mediated by the indenediide Pd complex (the iPr groups at P are omitted
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for clarity) in the presence of a second carbamic acid molecule in DMSO (Pd in light blue, S in
yellow, P in orange, O in red, N in dark blue).
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The reaction starts by side-on coordination of the substrate to the Pd center. In the active species
Cat, the triple bond is bound in an η2 fashion and oriented perpendicular to the SCS coordination
plane of Pd. The carbamic moiety is engaged in O−H∙∙∙O hydrogen bonding with the second
molecule of carbamic acid whose acidic proton weakly interacts with the electron-rich backbone
of the SCS ligand. The first step of the reaction is the protonation of the indenediide moiety.
Thanks to the network of hydrogen bonds, the corresponding activation barrier is low (8.2
kcal.mol-1 in enthalpy). The second molecule of carbamic acid acts as a proton shuttle and mediates
the proton transfer from the side-on coordinated substrate to the ligand backbone. Following the
intrinsic reaction coordinate, intermediate int-A is obtained. Then, cyclization occurs by
nucleophilic attack of the carbamic acid moiety to the π-activated triple bond with concomitant
proton transfer to the external molecule of carbamic acid. The outer-sphere approach of the
nucleophile controls the stereochemistry of the reaction, Z products being selectively obtained
from substrates bearing internal alkynes. The corresponding transition state TSB is the highest
point of the reaction profile in energy, making this 5-exo cyclization process the rate-determining
step of the overall transformation.39 The corresponding activation barrier was estimated to 21.8
kcal.mol-1 in enthalpy (22.4 kcal.mol-1 in Gibbs energy) in line with a relatively fast reaction under
mild heating, as observed experimentally.40 In the ensuing Pd species int-B, the oxazolidinone
ring is formed and bound to palladium via a σ Pd–C bond. The external molecule of carbamic acid
is weakly hydrogen-bonded to the ligand backbone and Pd center, ready to promote the back
transfer of a proton from the indenyl moiety to the cyclized substrate. It acts again as a proton
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shuttle and makes this protonolysis a low-activation barrier process (TSC, 12.9 kcal.mol-1 in
enthalpy). This step regenerates the indenediide pincer complex and yields the final oxazolidinone
product which remains weakly bound to the palladium center via side-on coordination of the
exocyclic double bond. Then, the oxazolidinone is released and replaced by another substrate
molecule, making turnover possible. Overall, the cyclization of the carbamic acid is highly
exothermic / exergonic (∆H and ∆G values of about 31 kcal.mol-1).
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These calculations confirm the participation of the indenediide moiety (by temporary fixation of
a proton) in this transformation and highlight the key role of a second external molecule of
carbamic acid, which acts as a proton relay and mediates proton transfers from the carbamic acid
substrate to the ligand backbone and after cyclization has occurred, from the ligand backbone to
the vinyl Pd moiety.41 This scheme parallels that we reported previously for the cycloisomerization
of alkynoic acids and N-tosyl alkynylamides.23 The carboxylative cyclization of propargylamines
generalizes and extends the scope of metal-ligand cooperativity with such SCS indenediide pincer
complexes. The computational study also emphasizes and explains the influence of DMSO. A
much higher activation barrier was computed in the gas phase for the rate-determining step of the
reaction profile (∆H≠ 33.4 kcal.mol-1).24,42 The high polar character of DMSO apparently plays a
key role in stabilizing the key transition state TSB. Consistently, a huge dipolar moment was
computed for TSB (18.6 D) as to compare with the reactants (3.4 D for Cat).
Conclusion
In summary, we have shown in this study that indenediide-based Pd SCS pincer complexes are
competitive with known catalysts to promote the carboxylative cyclization of propargylamines.
The bench-stable Pd dimer I enables straightforward, atom-economic and high-yield preparation
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of alkylidene-oxazolidinones under mild conditions (0.5-1 bar of CO2, DMSO, 40-80°C, 1-5
mol% Pd loading). It works with a wide range of propargylamines, including hitherto challenging
substrates such as secondary propargylamines bearing tertiary alkyl groups at nitrogen, primary
propargylamines and propargylanilines. Valuable information on the catalytic cycle have been
gained thanks to detailed NMR and DFT studies. Accordingly, DMSO, the very preferred solvent
for this transformation, was found to readily split the dimer I and coordinate to Pd to form a labile
adduct which is actually the resting state of the catalytic cycle. The high polarity of DMSO also
comes into play to lower the activation barrier of the rate-determining cyclization step.
Furthermore, the indenediide backbone of the ligand actively participates in the transformation by
temporarily fixing a proton and facilitating thereby the nucleophilic attack of the carbamic acid to
the side-on coordinated C≡C triple bond (metal-ligand cooperation). Last but not least, proton
shuttling appears essential at all stage of the transformations, from the initial amine carboxylation
(which is assisted by a second molecule of amine) to the back and forth proton transfers between
the ligand backbone and the organic fragment at Pd (which are assisted by a second molecule of
carbamic acid).43 By analogy and extension of what we reported for the cycloisomerization of
alkynoic acids,23 it is conceivable and very attractive to use H-bond donors as external additives
acting as proton relays. However the high polarity of DMSO and its propensity to form relative
strong H-bonds may mitigate the impact of such additives. The preliminary tests we performed in
this regard support this view. Indeed, the conversion of the sterically hindered propargylamine 1c
into the corresponding oxazolidinone 2c with the Pd dimer I was significantly speeded up upon
addition of 5 mol% of pyrogallol (97% conversion was reached after 20 h at 1 mol% Pd loading
and 70°C, instead of 90 h in the absence of additive).24 However, less effect was observed with
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other substrates such as 1h (a secondary propargylamine bearing an internal alkyne) in terms of
activity as well as selectivity.24
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Future work from our group will seek to develop further the chemistry of indenediide-based
pincer complexes and extend their catalytic applications, with special interest for transformations
involving metal/ligand cooperativity.
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AUTHOR INFORMATION
Corresponding Author
*bmv@chimie.ups-tlse.fr
*dbouriss@chimie.ups-tlse.fr
Notes
The authors declare no competing financial interest.
Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript.
Funding Sources
Any funds used to support the research of the manuscript should be placed here (per journal
style).
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ASSOCIATED CONTENT
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Supporting Information. Electronic Supplementary Information (ESI) available: Experimental
and computational details, characterization data including NMR spectra (PDF), optimized
structures (XYZ). This material is available free of charge via the Internet at http://pubs.acs.org.
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ACKNOWLEDGMENTS
This work was supported financially by the Centre National de la Recherche Scientifique, the
Université de Toulouse, the Agence Nationale de la Recherche (ANR CE6-CYCLOOP) and the
COST Action CM1205 CARISMA (Catalytic Routines for Small Molecule Activation). The
authors are grateful to CalMip (CNRS, Toulouse, France) for calculation facilities. L. M. thanks
the Institut Universitaire de France. Dr. J. Babinot is acknowledged for the preparation of
substrates 1j,k. This manuscript is in memory of Prof. José Barluenga.
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mol% Pd loading.24
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Based on mechanistic studies, this difference was attributed to the faster protodeauration
of the vinyl gold intermediates when substituted by alkyl rather than aryl groups.
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products, but the exact structure of the by-products could not be further established.
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29. Increasing the pressure of CO2 to 8 bar at 40°C did not change the outcome of the reaction
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with our Pd complex I, only cyclo-hydroamination was observed.
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30. Transformation of the corresponding N-Boc homopropargylamines catalyzed by a gold(I)
catalyst leads to the same products under mild conditions but with less atom-economy. See:
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31. Carboxylative cyclization of N-propargylanilines has been reported only once, using
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Chem. 2005, 70, 7795–7798.
32. Efficient preparation has been reported from the corresponding N-Boc propargylamines
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34. This conclusion was further supported by a competitive experience in which DMSO was
added to an equimolar mixture of I and IV in CDCl3 (Figure S4). After addition of 2 eq of
DMSO per metal center, the Pt dimer was fully converted into the corresponding
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