Copper-Catalyzed Hydroamination of N-Allenylazoles: Access to Amino-Substituted N-Vinylazoles

Article abstract of DOI:10.1002/adsc.201700965

Building on mechanistic studies, the innate capability of azoles to act as a directing group has been exploited to design an efficient and simple procedure for the hydroamination of N-allenylazoles with secondary amines. The reaction proceeds under mild conditions by copper(I) catalysis yielding the corresponding original linear E allylic amines with total regio- and stereoselectivity. Density Functional Theory (DFT) calculations offer a mechanistic explanation of the significantly higher reactivity of N-allenyl-(1,2)-azoles compared to their 1,3-analogues as a result of the reaction-enhancing coordination of the pyridine-like nitrogen to the copper center. (Figure presented.).

Full text of DOI:10.1002/adsc.201700965

Title: Copper-Catalyzed Hydroamination of N-Allenylazoles: Access to
Amino-Substituted N-Vinylazoles
Authors: Luca Alessandro Perego, Rémi Blieck, Julie Michel, Ilaria
Ciofini, Laurence Grimaud, Marc Taillefer, and Florian
Monnier
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10.1002/adsc.201700965
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Copper-Catalyzed Hydroamination of N-Allenylazoles: Access
to Amino-Substituted N-Vinylazoles
Luca Alessandro Perego,a, b,+ Rémi Blieck,c,+ Julie Michel,c Ilaria Ciofini,a,* Laurence
Grimaud,b,* Marc Taillefer c,* and Florian Monnier c, d,
*
a
Chimie ParisTech, PSL Research University, CNRS, Institut de Recherche de Chimie Paris (IRCP), 75005 Paris,
France. E-mail : ilaria.ciofini@chimie-paristech.fr
b
c
PASTEUR, Département de Chimie, École Normale Supérieure, PSL Research University, Sorbonne Universités,
UPMC Univ. Paris 06, CNRS, 75005 Paris, France. E-mail : laurence.grimaud@ens.fr
Ecole Nationale Supérieure de Chimie de Montpellier, Institut Charles Gerhardt Montpellier UMR 5253 CNRS,
AM2N, 8 rue de l’Ecole Normale, Montpellier 34296 Cedex 5, France. E-mail : marc.taillefer@enscm.fr;
florian.monnier@enscm.fr
d
Institut Universitaire de France, IUF, 1 rue Descartes, 75231 Paris cedex 5, France.
These two authors contributed equally to this work.
+
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
copper-catalyzed intermolecular hydroamination of
Abstract. Building on mechanistic studies, the innate
capability of azoles to act as a directing group has been aliphatic and aromatic terminal allenes with Cu(OTf)2
exploited to design an efficient and simple procedure for
the hydroamination of N-allenylazoles with secondary
amines. The reaction proceeds under mild conditions by
copper(I) catalysis yielding the corresponding and original
at 80 °C.[9] In
a
recent study, mechanistic
investigations revealed the prominent role of the in
situ-formed Cu(I) as catalytically active species and
spurred the extension of this reaction to allenamides
under mild conditions at room temperature with a
cationic Cu(I) catalyst.[10] One of the key factors for
the success of this reaction under milder conditions
was the effect of the coordination of copper by the
oxygen atom of the allenamide (Scheme 1).
Capitalizing on this concept of anchimeric assistance,
we decided to explore the latter by testing others
directing groups anchored on the allene. Thus we
aimed to extend this chelating-assisted catalysis to
other classes of substrates having a built-in nitrogen
coordinating moiety, and namely N-allenylazoles
(Scheme 1).
linear
stereoselectivity. Density Functional Theory (DFT)
calculations offer mechanistic explanation of the
E
allylic amines with total regio- and
a
significantly higher reactivity of N-allenyl-(1,2)-azoles
compared to their 1,3-analogues as a result of the reaction-
enhancing coordination of the pyridine-like nitrogen to the
copper center.
Keywords: Allenes; copper; hydroamination;
homogeneous catalysis; reaction mechanisms
Currently,
hydroamination
of
unsaturated
compounds is one of the most straightforward and
atom-economical pathways to generate amines from
simple substrates. Due to its high activation barrier,
hydroamination reactions require a catalyst, often
based on early- or late-transition metals, or alkali
earth metals.[1] Among the numerous reports
describing hydroamination, allenes are used much
less often than alkynes and alkenes, even if some of
them are readily available.[2] Catalytic systems based
on Pd,[3] Pt,[4] Au,[5] Rh[6], Ni[7] or Ag[8] are able to
perform intermolecular hydroamination of allenes
with the selective formation of linear or branched
allylic amines. In 2016, our group reported the first
Scheme 1. Hydroamination of allenes derivatives
featuring innate directing groups.
1
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10.1002/adsc.201700965
Advanced Synthesis & Catalysis
Herein we report the hydroamination of N-
allenylazoles catalyzed by Cu(I) under smooth
conditions. This powerful methodology allows the
synthesis of original N-vinylazoles bearing an amino
substituent at the allylic position, with excellent
regio- and E stereoselectivities.
We initially began our study by selecting 1-allenyl-
1H-benzotriazole 1 and morpholine a as the model
substrates. First we wanted to confirm the feasibility
of the reaction under the previously reported
conditions.[10-11] The use of
5
mol
%
of
[Cu(NCMe)4]PF6 at room temperature using only 1.2
equivalents of the amine partner provided the desired
hydroaminated product 1a with 84% yield in only 15
min (Scheme 2).
With these smooth conditions in hand, we then
explored the scope and limitations of this novel
reaction. A set of seven different N-allenyl-(1,2)-
azoles (1-7) was tested as summarized in scheme 2.
In all the cases, the corresponding E allylic amines
were isolated in good yields. No detectable amounts
of the Z amine or other isomeric products were
formed, as assessed by 1H NMR spectroscopic
analysis of the crude reaction mixtures. Allenes
substituted by benzotriazole 1 and 3, pyrazole 2 and 7,
indazole 4, triazoles 5 and 6 are suitable partners for
this reaction. Hydroaminated products 1a, 4a and 5a
containing morpholine were obtained in very short
reaction times with good yields. Allenylpyrazoles 2
required a longer reaction time to obtain similar
results (Scheme 2, 2a). It is worth noting that these
reaction conditions are efficient after 4 h for a large
array of amine partners such as cyclic (a-e), open-
chain (f-j), bis(allylic) k, and sterically hindered
amines (c and l). Unfortunately, no reaction took
place when primary amines were employed as
substrates.
aReaction conditions: 1-7 (1 equiv), a-l (1.2 equiv),
[Cu(NCMe)4]PF6 (5 mol %), THF, argon. Isolated yields.
Scheme 2. Cu-catalyzed hydroamination of N-allenyl-
(1,2)-azoles.a
In a second set of experiments, we decided to
extend the methodology to N-allenyl-(1,3)-azoles and
their benzo-fused analogues (Scheme 3), unable to
provide anchimeric assistance (Scheme 1). Within
this class of substrates, the reactivity is strikingly
variable.[8] When N-allenylbenzimidazole 8 was
reacted with morpholine in the presence of
[Cu(NCMe)4]PF6, (5 mol%), it took 48 h of reaction
to obtain the desired product 8a in 73% yield. On the
other hand, N-allenylimidazoles 9 and 10 are
significantly less reactive. Almost no reaction takes
place at room temperature and heating the reaction
mixture at 60 °C for longer time is needed to obtain
the corresponding products 9a-b and 10a.
Irrespective of reaction rate, yields are good to
excellent.
R
R
N
N
•
[Cu(NCMe)4]PF6
5 mol%
Y
N
N
N
HN
Y
+
THF
48-72 h
rt or 60 °C
a-b
8 - 10
N
N
N
N
O
O
O
N
N
N
N
N
N
N
N
8a, 73%
9a, 96%
9b, 69%
10a, 72%
48 h, rt
48 h, 60 °C
48 h, 60 °C
72 h, 60 °C
2
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10.1002/adsc.201700965
Advanced Synthesis & Catalysis
aReaction conditions: allene 8-10 (1.0 equiv), a-b (1.2
equiv), 5 mol % of [Cu(NCMe)4]PF6, THF, argon. Isolated
yields.
R'
•
A
R'
H
[CuI(NHR2)3]+
R2NH +
H
NR2
R2NH
P
Scheme 3. Cu-catalyzed hydroamination of N-allenyl-
NHR2
Cu(NHR2)2
(1,3)-azoles.a
R'
H
R'
Cu(NHR2)2
•
I1
H
H
R2N
H
The trends in the reactivity of the heterocyclic
substrates considered herein are summarized in
Figure 1. Generally speaking, N-allenyl-substituted
azoles featuring a second nitrogen atom at position 2
are more reactive than imidazoles and benzimidazole
is more reactive than imidazole.
TS_PDM
R2NH
R2NH
Cu(NHR2)2
R'
Cu(NHR2)2
R'
H
•
H
R2HN
H
H
H
H
NHR2
I2
TS_HA
R
R
R
R
Z
N
N
N
N
N
N
N
>>
>
N
Scheme 4. Catalytic cycle for the Cu-catalyzed
hydroamination of allenes. [10]
•
•
•
•
1, 2, 4, 5
8, 9
8
9
R = H or R = -(CH)4- Z = CH or N
With reference to the heterocyclic moiety, two
conformers of the relevant transition state are
possible, featuring a proximal or a distal relationship
between Cu and the YZ moiety of the heteroaromatic
ring (Figure 2). If Y=N, complexation to the copper
center is possible only in the proximal configuration,
and it can stabilize the transition state, similarly to
what happens for the oxygen atom of the amide in the
case of allenamides (cf. Scheme 1). [10]
Figure 1. Reactivity trends for the hydroamination of
different N-allenylazoles.
In order to explain these trends and confirm our
initial working hypothesis on the role of the second N
atom as an additional coordination site for the
catalyst, we engaged in theoretical mechanistic
studies, which were performed at Density Functional
Theory (DFT) level. Four model substrates were
chosen: N-allenyl-1H-pyrazole (2), N-allenyl-1H-
imidazole (9), N-allenyl-1H-indazole (4), N-allenyl-
1H-benzimidazole (8). Compounds 2 and 4 are
representative of 1,2-azoles, 8 and 9 of 1,3-azoles; 4
and 8 are benzo-fused, while 2 and 9 are not.
Z
Z
Y
Cu(a)2
Cu(a)2
Y
N
N
H
H
H
•
•
H
H
N
H
N
H
H
Consistently with what we have demonstrated in our
previous study concerning the hydroamination of
allenamides,[10] the reaction takes place by a rate-
limiting antiperiplanar attack (with respect to copper,
Scheme 4) of the amine on the cationic allene/Cu(I)
complex I1 via transition state TS_HA.[12] This
process leads to the Z alkenylcopper intermediate I2,
which in turn gives the trans alkene P after
stereospecific proto-demetallation with retention of
configuration via TS_PDM.
O
O
antiperiplanar attack
giving the Z organocopper intermediate,
proximal relationship between YZ and Cu
antiperiplanar attack
giving the Z organocopper intermediate,
distal relationship between YZ and Cu
Figure 2. Schematic representation of the two possible
conformers of the transition state for the hydroamination of
N-allenylazoles.
The transition states depicted in figure 2 have been
located by DFT calculations for all four model
compounds (2, 4, 8 and 9), so that the energetics of
the rate-limiting step of the catalytic reaction could
be assessed (Figure 3, see the Supporting Information
for computational details and additional data).
3
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10.1002/adsc.201700965
Advanced Synthesis & Catalysis
Computed thermodynamic parameters for the
isomerization of the Cu/allene complexes support this
view, since π-to-N isomerization is less favorable for
8 than for 9 (Figure 5).
.
.
.
.
a
N
N
N
N
•
Cu
•
•
•
a
N
N
Cu
a
a
N
N
N
N
N
N
N
N
Cu
a
Cu
a
a
4
2
a
8
9
N
N
[(8)Cu(a)2]+
DG = -5.5 kcal mol-1 DH = -1.6 kcal mol-1
[(9)Cu(a)2]+
DG = -7.7 kcal mol-1 DH = -3.7 kcal mol-1
Figure 3. Energetics of the transition states for the
hydroamination of model substrates with morpholine.
Gibbs free energies calculated at the DFT level are
reported in kcal mol-1 for both proximal and distal
conformers, with reference to the uncoordinated allene,
amine a and the complex [Cu(a)2]+, which have been set to
zero.
Figure 5. Competition for N- and π-coordination for 8 and
9. Computed thermodynamic parameters at the DFT level
are reported.
In summary, we demonstrated that the synthesis of
unprecedented linear allylic amines bearing N-
heterocycles (amino-substituted N-vinylazoles) can
From the transition state energies shown in Figure 3,
it is clear that in the proximal conformation the
activation barrier for the case of 1,2-azoles (2 and 4)
is significantly lower than the one of their 1,3-
analogues (9 and 8). Inspection of the geometries of
the transition state confirms the anticipated
coordination of the pyridine-like nitrogen of pyrazole
2 in the proximal-type transition state, while this is
not possible for imidazole 9 (Figure 4). Moreover, the
transition state for 2 is significantly more product-like
than that of 9, as can be inferred by comparing the
length of the newly forming C-N bond (2.05 Å vs
2.20 Å, respectively).
be
achieved
through
copper-catalyzed
hydroamination reaction involving N-allenylazoles
and a large array of aliphatic amines. Smooth
conditions and low catalytic loading of a readily
available copper(I) complex make this cost-effective
strategy very attractive in terms of atom- and step-
economy. Insights provided by DFT calculations,
showed that the pyridine-like nitrogen of N-allenyl-
(1,2)-azoles greatly contributes to a more effective
catalysis by coordination to the copper atom.
Continuous studies to extend the substrate scope of
this reaction are ongoing in our laboratory.
Experimental Section
For detailed experimental information, computational
details and the full characterization of all new N-
vinylazoles, see the ESI.
General procedure for Hydroamination of N-
allenylazoles: An NMR tube (5 mm diameter) or a
Schlenk flask of appropriate size was charged with
Cu(NCMe)4PF6 (0.05 equiv) and closed with a rubber
septum. After evacuation and back-filling with argon for
three times, dry THF (1 mL per mmol of N-
allenylheterocycle), the required secondary amine (1.2
equiv) and the N-allenylazole (1.0 equiv) were sequentially
Figure 4. Transition states for the hydroamination of 2 and
9 (proximal-type conformer shown), as obtained by DFT
modeling.
added. The vessel was shaken until
a completely
homogeneous solution resulted and the mixture was stirred
at room temperature until conversion was complete, as
checked by 1H NMR. The vessel was opened to the air, the
content was poured into 10 volumes of ethyl acetate and
partitioned with 3 volumes of saturated NaCl aqueous
solution. The aqueous phase was back-extracted with ethyl
acetate (3 x 3 volumes) and the combined organic phases
were exsiccated over Na2SO4. Volatiles were evaporated
under reduced pressure and the residue was purified by
flash chromatography on NaHCO3-treated silica gel to
afford the required hydroamination product.
In the case of 1,3-azoles, coordination of copper by
the pyridine-like nitrogen is not a reaction-enhancing
event as it is for pyrazoles, but it is a pathway that
competes with productive allene π-coordination.
Moreover, energetics of the transition state alone may
not be the only reason for the enhanced reactivity of
benzimidazole 8 compared to imidazole 9. A possible
further contribution to this disparity is that the
pyridine-like nitrogen of benzimidazole is less
available for coordination than the one of imidazole
(in agreement with the observation that the latter is a
weaker base),[13] so unproductive N-coordination is
less favorable for the benzannelated heterocycle.
Acknowledgements
Financial support provided by Région Languedoc-Roussillon
(PhD fellowship for RB), IUF (Institut Universitaire de France
4
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10.1002/adsc.201700965
Advanced Synthesis & Catalysis
for FM), ANR CD2I (project CuFeCCBond), ENSCP, ENS and
CNRS is warmly acknowledged.
not allow the formation of the expected product when
6-chloro-9-allenyl-9H-purine was engaged neither at rt
nor at 60 °C.
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–
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[12] As in with our previous work,[10] Cu(I) complexes
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Heterocyclic Chemistry 5th ed., Wiley: Chichester (UK),
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The conditions described in the present publication did
5
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10.1002/adsc.201700965
Advanced Synthesis & Catalysis
UPDATE
Copper-Catalyzed Hydroamination of N-
Allenylazoles: Access to Amino-Substituted N-
Vinylazoles
Adv. Synth. Catal. Year, Volume, Page – Page
Luca Alessandro Perego, Rémi Blieck, Julie
Michel, Ilaria Ciofini,* Laurence Grimaud,* Marc
Taillefer* and Florian Monnier*
6
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