Calcium(II)-Catalyzed Intra- and Intermolecular Hydroamidation of Unactivated Alkenes in Hexafluoroisopropanol

Article abstract of DOI:10.1021/acscatal.7b04271

A combination of a calcium(II) triflimide salt and hexafluoroisopropanol (HFIP) was found to be a highly efficient promoter system for the intra- and intermolecular hydroamidation of unactivated alkenes. Unlike other methods, a vast array of functional groups is tolerated at the nitrogen and alkene moieties. The reaction produces the corresponding nitrogen-containing compounds in excellent yields and good diastereoselectivities. The use of HFIP as solvent proved crucial for the proper carrying out of this transformation. Its role, as well as that of calcium and its NTf₂ ligand, was rationalized by DFT computations. These calculations show how the [(NTf₂)Ca(HFIP)_n]⁺ complex can activate the amide via a basic site of the NTf₂ ligand and the alkene with one acidic HFIP proton. The acidity of HFIP is exacerbated by the coordination to the calcium center, the more so as n increases.

Full text of DOI:10.1021/acscatal.7b04271

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Article
Calcium(II)-Catalyzed Intra- and Intermolecular Hydroamidation
of Unactivated Alkenes in Hexafluoroisopropanol
Chenxiao Qi, Felix Hasenmaile, Vincent Gandon, and David Leboeuf
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b04271 • Publication Date (Web): 18 Jan 2018
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ACS Catalysis
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Calcium(II)-Catalyzed Intra- and Intermolecular Hydroamidation of
Unactivated Alkenes in Hexafluoroisopropanol
Chenxiao Qi,a Felix Hasenmaile,a Vincent Gandon*,a,b and David Lebœuf*,a
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a Institut de Chimie Moléculaire et des Matériaux d’Orsay (ICMMO), CNRS UMR 8182, Université Paris-Sud, Université
Paris-Saclay, Bâtiment 420, 91405 Orsay cedex, France.
b Laboratoire de Chimie Moléculaire (LCM), CNRS UMR 9168, Ecole Polytechnique, Université Paris-Saclay, route de
Saclay, 91128 Palaiseau cedex, France.
ABSTRACT: A combination of a calcium(II) triflimide salt and hexafluoroisopropanol (HFIP) was found to be a highly efficient
promoter system for the intra- and intermolecular hydroamidation of unactivated alkenes. Unlike other methods, a vast array of
functional groups is tolerated at the nitrogen and alkene moieties. The reaction produces the corresponding nitrogen-containing
compounds in excellent yields and good diastereoselectivities. The use of HFIP as solvent proved crucial for the proper carrying out
of this transformation. Its role, as well as that of calcium and its NTf2 ligand, was rationalized by DFT computations. These calcula-
tions show how the [(NTf2)Ca(HFIP)n]+ complex can activate the amide via a basic site of the NTf2 ligand, and the alkene with one
acidic HFIP proton. The acidity of HFIP is exacerbated by the coordination to the calcium center, the more so as n increases.
Keywords: hydroamidation, calcium, hexafluoroisopropanol, alkenes, heterocycles, DFT computations.
EWG
Introduction
H
R
N
alkene activation
Y
MLn
Pyrrolidines and piperidines are ubiquitous nitrogen-
containing heterocycles in crop science and medicinal chemis-
try.1 Over the last half-century, their construction has been a
fascinating topic for chemists, and has triggered the develop-
ment of new catalytic systems, ever more efficient and selec-
tive. Among the numerous methods described towards their
synthesis, hydrofunctionalization of alkenes, including hy-
droamination and hydroamidation, holds a salient position,2,3
providing an efficient and atom-economical route for the prep-
aration of these highly valuable scaffolds. In this respect,
tremendous efforts have been devoted to the development of a
large variety of versatile transition-metal-,4 Lewis5 and
Brønsted6 acid-, and organic7-based catalytic systems in order
to enable the hydroamidation of unactivated alkenes via either
the activation of the alkene or that of the amine (Scheme 1).
However, despite remarkable progress made in this field,
several major challenges remain to be addressed. For instance,
most of these methods are extremely dependent on the nitro-
gen protecting group. Those that display a high Lewis basicity
can preclude the hydroamidation because of a strong interac-
tion between the catalyst and the nitrogen functionality.
Among other drawbacks, we can also cite the difficulty to
activate styrene derivatives bearing strong electron-
withdrawing groups and, on the other hand, the too high reac-
tivity of styrenes bearing electron-donating groups, which can
lead to side-reactions such as self-polymerization.2,3 All these
limitations restrict the access to molecules of potential interest.
In this context, devising a robust and simple catalytic system,
that could circumvent most of these problems, without having
to rely on precious transition-metals, is highly sought-after.
Fe,4a-b Cu,4f
Pd,4g-h Ag,4i
Ir,4j,4l Pt,4m-n
Au4o-v
EWG
H
N
R
Co4d
Y
EWG
N
Common drawbacks:
Y
Y
R
- expensive catalytic systems
- limited alkene-substitutions
- limited N-protecting groups
- poor diastereoselectivity
EWG
H
and/or
EWG
N
R
Y
N
R
B,5d
Nb,5e
MLn
EWG
Bi,5a-c
R
N
H
Sc,5b-c
6
Fe,4c Ir,4k IBX,7a
acridinium7b-c
H
Y
EWG
N
R
amine activation
Y
This work:
EWG
N
EWG
R4
R4
and/or
R1
R1
R2
R3
R2
N
H
Ca(NTf2)2
nBu4NPF6
N
Y
R1
Y
Y
EWG
R3
R3
n
R4
R2
n
n
H
EWG
HFIP
N
EWG
EWG
+
H2N
EWG
Scheme 1. Hydroamidation of unactivated alkenes.
Recently, we have demonstrated that the acidity of hex-
afluoroisopropanol (HFIP) could be significantly har-
nessed by calcium(II) salts in order to activate Csp3-O
bonds, outperforming common Lewis and Brønsted acids
in terms of activity and efficiency in the aza-Piancatelli
cyclization8 through the coordination of HFIP to calcium
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and the formation of H-bond clusters.9,10 Moreover, due
Page 2 of 8
array of
N-tosylaminoalkenes to access pyrrolidine or
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7
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its strong H-bond donor ability, HFIP has the capacity to
facilitate the release of Lewis acids trapped by unwanted
coordination to the substrate (or the product), allowing the
catalytic process to turn over.8a,10c We wondered whether
piperidine derivatives (Table 2). In general, the corre-
sponding products were obtained in good to almost quan-
titative yields within 2 hours at 80 °C in HFIP. It is note-
worthy that the gem-disubstituent effect does not seem to
play a critical role in terms of reaction rates (2b vs 2c).14
these abilities could be exploited in the activation of Csp2
-
C
sp2 bonds for the intra- and intermolecular hydroami-
In the case of 2,2-disubstituted N-tosylaminoalkenes (1d
dation of unactivated alkenes, while unlocking, in the
process, the reactivity of “challenging” substrates. Out-
lined herein is a new approach relying on an acidic
Ca(II)/HFIP combination that can grant a straightforward
access to a wide range of functionally diverse nitrogen-
containing derivatives.
and 1e), the reaction can even be performed at room tem-
perature to deliver 2d and 2e in 82% and 66% yield, re-
spectively. The reaction is also compatible with the pres-
ence of various secondary sulfonamides (1f and 1g) to
afford the products 2f and 2g in excellent yields and good
diastereoselectivities. In an attempt to specifically prepare
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piperidine derivatives, we studied the reactivity of
N-
tosylaminoalkenes 1h and 1i. However, under the reaction
conditions, pyrrolidines 2h and 2i were obtained as major
products, which suggest that the substrates experienced a
fast isomerization process before undergoing the hy-
droamidation step.5c This process can be slowed down by
using a less acidic solvent such as toluene (2h/2’h). On
the other hand, with a phenyl substituent at the alkene
moiety (1j), piperidine 2’j was obtained as a sole product.
Another interesting feature revolved around substrate 1k
While pyrrolidine 2g was exclusively formed in the ab-
sence of a gem-disubstituent effect, piperidine 2’k was
generated as a major product in its presence, thus, coun-
terbalancing the isomerization. In this case, using toluene
Results and Discussion
We began our investigations with
as a model substrate in the presence of a combination of
N-tosylaminoalkene 1a
Ca(NTf2)2 and nBu4NPF6 (5 mol%) (Table 1, entries 1-
6).11 The presumed role of the ammonium salt is to pro-
mote the formation of the [Ca(NTf2)]+[PF6]- species,12
which is more Lewis acidic than Ca(NTf2)2.12b Conduct-
.
ing the reaction in HFIP at 80 °C proved to be very effec-
tive to give rise to the corresponding pyrrolidine 2a in
95% yield with a good diastereoselectivity in favour of a
trans relationship (entry 1). Reactions ran in other sol-
vents proceeded at a slower rate with lower yields and
selectivities (entries 2-5). A series of control experiments
was also carried out to ascertain the necessity of each
component (ligand, catalyst and additive) (entries 7-10).
As anticipated, no reaction was observed in the absence of
as a solvent even led to the exclusive formation of 2’k
.
Table 2. Scope of intramolecular hydroamidation of
tosylaminoalkenes
N-
1.
Ca(NTf2)2 and/or n
Bu4NPF6.13
Table 1. Reaction optimization for the formation of pyrroli-
dine 2a.
Yield 2a
Entry
Catalyst
Additive
Solvent
t [h]
[%]
(trans/cis)
1
Ca(NTf2)2
Ca(NTf2)2
Ca(NTf2)2
Ca(NTf2)2
Ca(NTf2)2
Ca(NTf2)2
Ca(OTf)2
Ca(NTf2)2
-
nBu4NPF6
nBu4NPF6
nBu4NPF6
nBu4NPF6
nBu4NPF6
nBu4NBF4
nBu4NPF6
-
HFIP
1
95 (4.8:1)
87 (2.8:1)
60 (3.5:1)
88 (2.5:1)
81 (4:1)
90 (4.4:1)
NR
2
1,2-DCE
Toluene
MeNO2
TFE
4
3
4
4
4
5
2
6
HFIP
1.5
4
7
HFIP
8
HFIP
4
NR
9
nBu4NPF6
-
HFIP
4
NR
10
-
HFIP
4
NR
Having identified the best reaction conditions, we sought
to explore the scope of this transformation using a broad
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especially for intramolecular reactions, and often required
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the use of transition metals to trigger the hydroamidation
step at the expense of the scope with reactions often lim-
ited to terminal alkenes.4-6 But, one of the major ad-
vantages of our methodology is its compatibility with a
large variety of
N-protecting groups, ranging from sul-
fonyl to (alkoxy)carbonyl and carbamoyl (Table 3), which
was a recurrent issue in intramolecular hydroamidations
with Lewis and Brønsted acids.5,6 In each case, the desired
pyrrolidine was obtained in good to high yields (up to
95%), without having to resort to precious metals, whose
use, incidentally, is often limited to the hydroamidation of
terminal alkenes. Regarding our exploration studies, the
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only exception was the
N-tert-butyloxycarbonylamino
alkene 3h. Indeed, we noticed that, during the course of
the reaction, the protecting group was partially cleaved to
generate the corresponding free amine, precluding the
hydroamidation because of a presumed strong coordina-
tion to calcium. However, replacing the
N-tert-
butyloxycarbonyl group by the less sensitive fluorenylme-
thyloxycarbonyl group proved to be beneficial for the
restoration of the reactivity (4g, 88% yield). Of note, the
use of common solvents such as toluene, nitromethane
and 1,2-dichloroethane was ineffective with substrates
4d-4i. It is also worth mentioning that the tosyl group
from 4a can be easily removed in the presence of magne-
sium powder in methanol (under sonication) to provide 2-
phenylpyrrolidine 4j in 85% yield (see Supporting Infor-
mation for details).
Table 3. Influence of N-protecting groups on the reactivi-
ty.
[a] Reaction in the presence of Ca(NTf2)2 (10 mol%) and nBu4NPF6 (10 mol%). Boc
= tert-butyloxycarbonyl. Fmoc = fluorenylmethyloxycarbonyl.
Interestingly, the reaction could also be extended to the
substrate
withdrawing groups on the nitrogen, to give the corre-
sponding lactam derivative in 53% yield (Equation 1).
5, featuring the presence of two electron-
As mentioned in the Introduction, nitrogen-protecting
group that display a strong Lewis basicity can prevent the
hydroamidation step by trapping the catalyst. This is why
sulfonamides have been primarily reported, but removing
the sulfonyl protecting group can be sometimes a tedious
task. On the other hand, carbamates, carboxamides and
ureas, which are easier to remove than sulfonamides,
proved to be more problematic in terms of reactivity,
6
The substitution pattern at the alkene moiety was then
evaluated (Table 4). To our delight, the reaction was tol-
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Page 4 of 8
erant to a large variety of functional groups (alkyl, naph-
more deactivated styrenes (10e and 10f), we found out that
using an excess of styrene derivative led to better yields.
1
2
3
4
thyl and (hetero)aryl) with yields ranging from 51% to
96%. In particular, we succeeded to achieve the hydroam-
idation in the presence of a strong electron-withdrawing
group such as CF3 in good yields, albeit at a slower reac-
Table 5. Scope of intermolecular hydroamidation of al-
kenes.[a]
tion rate. On the other hand, the p-nitrophenyl analogue
5
7d failed to provide 8d. Regarding the reactivity, we no-
ticed that the hydroamidation was extremely dependent
on the electronic nature of the functional groups. For
instance, in the presence of electron-richer groups, our
standard reaction conditions in HFIP proved to be detri-
mental to the reactivity (see Supporting Information for
details). However, this problem could be circumvented by
using a 1:3 combination of HFIP and toluene in order to
soften the reaction conditions, with the exception of com-
pound 8b, which required the sole use of toluene as a
solvent. We also found that we could access bicyclic
framework such as 8m in 62% yield.
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Table 4. Influence of alkene substitution on the reactivi-
ty.[a]
[a] Reactions conditions: N-tosylamine derivative 10a (3 equiv) and alkene 9 (1
equiv) in HFIP (0.2 M) in the presence of Ca(NTf2)2 (10 mol%) and nBu4NPF6 (10
mol%) at the indicated temperature. [b] N-tosylamine derivative 10a (1 equiv) and
alkene 9 (3 equiv). [c] Ca(NTf2)2 (20 mol%) and nBu4NPF6 (20 mol%).
The mechanisms involved in Lewis acidic salt-catalyzed pro-
cesses are still not fully understood. In many cases, the reac-
tions are quenched or strongly slowed down in the presence of
a proton scavenger, which suggests that hidden Brønsted acid
catalysis is taking place.15 However, it is also clear that the
metal is indispensable, since the direct use of Brønsted acids is
often not as efficient as with the metal salt.15c Another im-
portant point is that the reaction of Ca(NTf2)2 with nBu4NPF6
produces [Ca(NTf2)]+[PF6]-12 rather than species in which both
-
NTf2 ligands would have been replaced, such as [Ca]2+[PF6]2
.
16
The NTf2 ligand is actually a polybasic fragment (through
its nitrogen atom and its sulfonyl oxygens) that should not be
neglected.17 The study of the reaction mechanism by means of
DFT computations offered us a unique opportunity to relate
the metal, the NTf2 ligand, and protons coming from HFIP.
The calculations were carried out using the Gaussian 09 soft-
ware package.18 The results presented are ꢀG298 in kcal/mol
obtained at the M06-2X/6-31+G(d,p) level of theory. The
solvation model based on density (SMD) was used to take the
solvent effect into account, using the parameters of 2-
propanol, except ε set at the HFIP value of 16.7.19 Compound
1a was used as model substrate. Since Ca(NTf2)2 is known as
an 8-coordinate tetrahydrate in the solid state,20 and since no
special precautions are taken when using it, water molecules
were used to fill the coordination sphere of calcium. It is im-
portant to stress first that the activation of the C=C bond with
calcium to trigger the cyclization failed. On the other hand, we
succeeded in modeling the cyclization after introducing one
HFIP molecule as ligand to calcium and using its proton as
activator (Table 6).
The ligation of the substrate to the (NTf2)Ca+ moiety is actual-
ly achieved at a tosyl oxygen as in I. A non-covalent interac-
tion between the alkene and the OH group also contributes to
freeze the conformation of the substrate (the maximum elec-
tron density found in this area is ρmax ~ 0.02 e.Å-3 for each case
studied). However, a third association between the substrate
and the (NTf2)Ca+ moiety is also required. Provided the NTf2
ligand is oriented so as to establish a strong NH---OS hydro-
gen bond, the N-C bond formation to give ammonium II could
[a] Reactions conditions: N-tosylaminoalkenes 7a-7m in HFIP (0.2 M) in the pres-
ence of Ca(NTf2)2 (5 mol%) and nBu4NPF6 (5 mol%) at the indicated temperature.
[b] Reaction performed in toluene. [c] Reaction performed in toluene/HFIP (3:1).
Encouraged by these results, we turned our attention to inter-
molecular hydroamidations of alkenes, focusing on a less
reactive class of compounds, namely electronically deactivat-
ed styrene derivatives (Table 5). To date, the hydroamidation
of these types of compounds is unprecedented. Gratifyingly,
by using an excess of p-toluenesulfonamide 10a (3 equiv) in
the presence of 10 mol% of Ca(NTf2)2/nBu4NPF6, we suc-
ceeded to synthesize the desired N-benzyl sulfonamides 11a-
11d in good yields, while the formation of the desired prod-
ucts was not observed in other solvents (toluene, nitromethane
and 1,2-dichloroethane). On the other hand, in the case of even
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be achieved by HFIP-to-alkene proton transfer and concomi-
Figure 1. Geometry of the computed transition state cor-
responding to the trans cyclization (one water molecule
omitted for clarity)
1
2
3
4
5
6
7
8
tant attack of the nitrogen atom.
Table 6. Computed free energies.[a]
These results rationalize why HFIP is an appropriate solvent
for the title transformation. Once ligated to calcium, it will
become able to protonate the alkene. This is especially true if
the calcium center is not too electronically enriched, i.e. with
other HFIP molecules in its coordination sphere rather than
water molecules. Another important point is that the cycliza-
tion does not take place if the NTf2 ligand is not oriented so as
to interact with the NH group. The length of the forming N-C
bond is still long in the transitions state (2.51 Å with 3 HFIP),
but the NH---OS interaction contributes to its rigidification.
Overall, in such a model, a coordination site is required on the
EWG at the nitrogen, which can be found in any of the exam-
ples reported herein, and the substrate is confined through a
O
O
O
S
S
S
CF3
CF3
CF3
CF3
N
O
N
N
F3C
O
F3C
O
F3C
O
O
O
CaL4
O
O
CaL4
O
O
CaL4
O
S
S
S
O
O
S
S
S
O
O
O
O
O
N
H
H
CF3
CF3
N
N
H
H
CF3
CF3
CF3
I
II
III
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ꢀG‡
I)
(II- ꢀG298 (II- ꢀG298 (III-
Entry L4
Dias
298
I)
I)
1
2
3
4 H2O
4 H2O
trans
cis
33.9
34.3
32.5
6.5
6.7
0.5
-13.6
-15.8
-8.4
+
triple association with the (NTf2)Ca(HFIP)n fragment. The
HFIP/ 3 trans
metal has two roles: it unites the substrate, the NTf2 ligand and
HFIP, and it strengthens the acidity of the latter, which proved
to be crucial to activate styrenes usually unreactive towards
H2O
4
5
HFIP/ 3 cis
H2O
32.7
4.5
-14.8
+
hydroamidation. To some extent, (NTf2)Ca(HFIP)n can be
compared to a metal-templated hydrogen bonding bifunctional
organocatalyst.
2
trans
27.3
-1.2
-35.6
HFIP/
2 H2O
Conclusions
6
2 HFIP/ cis
31.4
4.6
-46.9
In summary, we have devised a novel catalytic strategy to
forge valuable nitrogen-containing derivatives through the
hydroamidation of unactivated alkenes. In particular, we used
the remarkable properties of HFIP as a solvent in combination
2 H2O
[a] kcal/mol, L = H2O.
However, a quite high free energy of activation of 33.9
kcal/mol was computed to obtain the trans product (entry 1).
The transformation yielded a calcium hydroxide in an ender-
gonic fashion (ꢀG298 6.5 kcal/mol). The transfer of the ammo-
nium proton to the hydroxide to regenerate HFIP led to III,
which is more stable than I by 13.6 kcal/mol. Forming the cis-
product through this mechanism proved slightly more de-
with
a catalytic Ca(II)-based Lewis acid to activate
challenging substrates and, therefore, trigger a hydroamidation
process. This methodology proved to be general and versatile,
while expanding the boundaries of the hydroamidation.
Further investigations are on-going to apply this catalytic
system to other transformations.
manding in free energy of activation (entry 2, ꢀG‡ 34.3
ASSOCIATED CONTENT
SUPPORTING INFORMATION
298
kcal/mol). With 2 HFIP molecules, ꢀG‡ decreased slightly
298
(entries 3 and 4). While the formation of the cis product re-
Experimental procedures and characterization data of all new
compounds (including NMR spectra), and DFT computations.
This material is available free of charge via the Internet at
http://pubs.acs.org/
mained endergonic, that of the trans became virtually ther-
moneutral. With 3 HFIP molecules (entries 5 and 6), ꢀG‡
298
decreased significantly (27.2 vs 31.4 kcal/mol). The formation
of the trans ammonium even became exergonic (-1.2 kcal/mol
vs 4.5 kcal/mol for the cis ammonium). The transition state
leading to the trans ammonium is displayed in Figure 1.
AUTHOR INFORMATION
Corresponding Authors
vincent.gandon@u-psud.fr
david.leboeuf@u-psud.fr
Authors’ Contributions
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the manu-
script.
Notes
The authors declare no competing interest.
ACKNOWLEDGMENT
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We gratefully thank the China Scholarship Council (CSC),
CNRS, Université Paris-Sud, and Institut Universitaire de
France (IUF) for the support of this work.
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