Anti-Markovnikov additions to N-allylic derivatives involving ammonium-carbenium superelectrophiles

Article abstract of DOI:10.1039/c2cc32246c

Anti-Markovnikov additions to non-conjugated unsaturated amines in superacid are reported. In situ NMR studies, DFT calculations and labelled substrates reactions support the involvement of new ammonium-carbenium superelectrophiles in this original proces

Full text of DOI:10.1039/c2cc32246c

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Anti-Markovnikov additions to N-allylic derivatives involving
ammonium–carbenium superelectrophileswz
Guillaume Compain,a Agnes Martin-Mingot,a Gilles Frapper,b Christian Bachmann,b
a
a
´
Marie-Paule Jouannetaud and Sebastien Thibaudeau*
Received 28th March 2012, Accepted 14th April 2012
DOI: 10.1039/c2cc32246c
Anti-Markovnikov additions to non-conjugated unsaturated amines
in superacid are reported. In situ NMR studies, DFT calculations
and labelled substrates reactions support the involvement of new
ammonium–carbenium superelectrophiles in this original process.
When product 3a was subjected to superacidic conditions, a
mixture of compounds 2a and 3a was formed, showing that
equilibria between their cationic precursors could occur. Thus,
after (poly)protonation in superacid, dicationic ammonium–
carbenium superelectrophiles could be considered as the inter-
mediates involved in the fluorination process (Scheme 1). The
Markovnikov product 2a and the anti-Markovnikov product
3a could, respectively, come from the nucleophilic trapping of a
secondary carbocation A (b position) and a primary carbocation
C (o position),8 as well as that of a non-classical intermediate
B (hydrido-bridged structure),9 a hypothesis which strongly
intrigued us. To test this hypothesis, the reactivity of N-allylic
anilines was examined both from experiments in superacid
(Table 1) and from density functional theory (DFT) calcula-
tions on these proposed Markovnikov and anti-Markovnikov
reaction intermediates. Our first purpose was to quench the
cationic intermediates with an aromatic nucleophile, through
an intramolecular cyclization process. First, substrate 1b was
reacted with the superacid at ꢀ50 1C, yielding mainly a
fluorinated product. Nevertheless, characterization of indoline
4b and tetrahydroquinoline 5b validated our approach (Table 1,
entry 1). We next screened various experimental conditions to
optimize the formation of the cyclic products. By increasing
the temperature of the media, the hydrofluorination process
could be decreased in favor of cyclization (Table 1, entry 2).
One of the most extensively studied chemical reactions of
CQC double bonds is the E–Nu addition (addition of an
electrophile, followed by nucleophilic trapping of the formed
carbocation).1 Most electrophilic additions follow the Markovnikov
rule,2 however, the rate and regioselectivity of the addition to
unsymmetrical alkenes are processes that are strongly influ-
enced by the double bond environment. Achieving control
over the regioselectivity of an addition is a crucial basis for
future innovations in this field. In this context, regioselective
anti-Markovnikov electrophilic additions to unsaturated nitrogen-
containing compounds remain a critical challenge.1,3,4 Herein, we
disclose an acid catalyzed anti-Markovnikov electrophilic addition
to non-conjugated unsaturated amines. In the course of our
studies on HF/SbF5 superacid chemistry,5 we already identified
a new reaction involving the hydrofluorination of unsaturated
amines6 after superelectrophilic activation.7 More recently,
we found that when starting from amine 1a, the unexpected
o-fluorinated product 3a was obtained in low yield, in addition
to b-fluoroamine 2a (Scheme 1).
a
Table 1 N-Allylaniline 1b behavior in HF/SbF5
Productsc,d
Scheme 1 Hydrofluorination of unsaturated amines in superacid
HF/SbF5 and hypothetical intermediates, precursors of the Markovnikov
2a and the anti-Markovnikov 3a products.
b
Entry
% mol SbF5
T/1C
2b
3b
4b
5b
e
e
e
e
e
1
2
3
4
5
3.8
3.8
12.1
21.6
21.6
ꢀ50
ꢀ20
ꢀ20
ꢀ20
0
86 (50)
23
3
—
—
—
—
—
1
28
43
51 (36)
57 (39)
3
45
46
33 (25)
36 (22)
a Superacid group in ‘‘Glycochimie, Superacide et Chimie des
`
´
Systemes’’ Team, Universite de Poitiers, CNRS UMR 7285 IC2MP,
3
—
e
4, rue Michel Brunet, F-86022 Poitiers Cedex, France
b Computational Chemistry Group in ‘‘Catalysis and Renewable
Carbon’’ Team, Universite´ de Poitiers, CNRS UMR 7285 IC2MP,
4, rue Michel Brunet, F-86022 Poitiers Cedex, France.
a
Reaction conditions: substrate (1 mmol), HF/SbF5 (4 mL), 10 min. The
b
starting material was observed in all cases (less than 10%). HF/SbF5
media composition defined by SbF5 molar percentage.10 c Relative
abundances determined by analysis of the 1H NMR spectra of the crude
E-mail: sebastien.thibaudeau@univ-poitiers.fr; Tel: +33 549454588
w This work is dedicated to Professor Jean-Claude Jacquesy.
z Electronic supplementary information (ESI) available: General
procedures, computational details and 1H and 13C NMR data. See
DOI: 10.1039/c2cc32246c
d
e
reaction. The isolated product yields are given in brackets. Only traces
of the product could be detected by 1H NMR in the crude mixture.
c
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Chem. Commun., 2012, 48, 5877–5879 5877

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a
Table 2 Reactivity of the N-allylic anilines in HF/SbF5
Substrates
Fig. 1 Proposed superelectrophile precursors as predicted from DFT
calculations (distances in angstrom).15
Entry
R1
R2
R3
Products (yield)b
Ratioc
¨
1
2
3
4
1b
1c
1d
1e
1f
1g
1h
1i
H
Me
CF3
NHAc
OMe
SO2NH2
NO2
H
H
H
H
H
H
H
H
NO2
H
H
H
H
H
H
H
H
H
Me
4b (39)
4c (46)
4d (5)
4e (17)
4f—d
5b (22)
5c (14)
5d (39)
5e (72)
5f (32)
5g (92)
5h (85)
5i (66)g
5j (84)
1.6/1
2.2/1
1/4.2
1/4.5
1/19.5
nde
these intermediates can be envisaged. The protonated nitrogen
atom and CC double bond site species are stationary points on
the potential energy surface but 7.7 kcal molꢀ1 higher in energy
than the most stable arenium–ammonium dication D (Fig. 1).
Even if a mechanism based on double bond protonation could
not be ruled out, a more favorable route to the cyclic compounds
would proceed through the formation of an arenium–ammonium
superelectrophile D. Then, our study focused on the mechanism
envisaged to explain the behavior of N-allyl-4-nitroaniline 1h in
superacid. In 1h, delocalization of the amino group electron pair
strongly favored a first protonation on the nitro group at the
oxygen atom; then, a second protonation occurred on the amino
group (Fig. 1). Interestingly, the calculated energies indicated
that a further protonation, on the double bond, would lead to a
triprotonated carbenium ion. This reaction was predicted to be
energetically more favorable (by more than 40 kcal molꢀ1) than
the protonation of the aromatic ring so that, for deactivated
substrates, the tetrahydroquinoline products would not arise
from the protonation of the aromatic ring.
5
6
4g (0)
4h (0)
4i (0)
7f
8f
9f
nde
nde
1j
NO2
4j (0)
nde
a
Reaction conditions: substrate (1 mmol), HF/SbF5 (4 mL, SbF5 mol% =
21.6), 0 1C. b Yield of the isolated product. c Molar ratio between 4 and 5
determined by analysis of the 1H NMR spectrum of the crude reaction.
d
Only traces could be detected in the crude mixture. e Not determined, as
no indoline was observed in the crude mixture. f Reaction time >8 hours.
g
5-Nitro-1,2,3,4-tetrahydroquinoline 5i0 was also formed in 10% yield.
A similar effect of the increase of acidity, that means the increase of
SbF5 concentration, on the selectivity of the reaction was observed
(Table 1, entries 3 and 4).10,11 Exclusive formation of the cyclic
compounds occurred under optimized conditions (Table 1, entry 5).
Then, the reactivity of various anilines (from the activated
ones to the strongly deactivated)12 was tested under the latter
conditions (Table 2). In all cases, tetrahydroquinoline derivatives
were formed. Starting from the activated aniline 1c, indoline 4c
and tetrahydroquinoline 5c were formed. An increase of the
inductive donating effect (Me, sp = ꢀ0.15)12 on the aromatic
ring increased the formation of the indoline product (Table 2,
entry 2). Electronically deactivated substrates were also tested.
Interestingly, a decrease of the electronic density on the
aromatic ring upon introduction of a trifluoromethyl group
(sp = 0.54) yielded tetrahydroquinoline 5d as the major
product (Table 2, entry 3).13 A similar behavior was observed
for anilines 1e and 1f when the aromatic ring was, respectively,
substituted with an amido or a methoxy group (Table 2,
entries 4 and 5) since, under such acidic conditions, the proto-
nated ether and amide functions, in equilibrium with their neutral
forms, could act as strong electron-withdrawing substituents.14
By increasing the withdrawing effects on the aromatic ring
(sp SO2NH2 = 0.6 and sp NO2 = 0.78)12 the reactivity was
shifted to the exclusive formation of the tetrahydroquinoline
product (Table 2, entries 6–8), even in the presence of a
supplementary methyl donating group (Table 2, entry 9).
DFT calculations were performed to complete our under-
standing of this chemistry.15 The clear behavioral differences
between activated and deactivated substrates in superacid
suggested that both N-allylaniline 1b and N-allyl-4-nitroaniline
1h should be tested as model substrates. The calculations predicted
that a first protonation of the substrate 1b occurred at the nitrogen
atom, and a second protonation occurred at the aromatic ring
(para, ortho, and meta positions, relative DGcalc. = 0.0, 1.3 and
3.1 kcal molꢀ1, respectively), resulting in the formation of
dicationic species. Note that, as the barrier for proton exchange
along the aromatic group is o2 kcal molꢀ1, equilibria between
Such a third protonation would produce a secondary carbenium
ion of type A (Scheme 1) but a second stationary point (energy
minimum) was located close in energy, at +1.1 kcal molꢀ1. This
optimized B0 structure (Fig. 1) involves a three-center two-electron
bond and corresponds to a symmetrically hydrido bridged species
(m-HꢁꢁꢁC distances: 1.33 A, activated CQC bond length: 1.39 A).
As a consequence, the selectivity of the formation of the
6-membered ring products, from deactivated substrates, could
be attributed to the relative stabilities of the Wheland inter-
mediates, E and E0, resulting from the cyclisation via trapping
of the intermediates A and/or B0 (Fig. 2). In this case, the
difference of energy between E and more-strained E0 inter-
mediates (DGcalc. = 4.4 kcal molꢀ1) could account for the
exclusive formation of the tetrahydroquinoline product.
To determine whether the experimental results could support
the formation of arenium–ammonium dications (such as D),
N-methylanilines 6, 7 and 8 were dissolved in superacid HF/SbF5
and characterized by low temperature NMR spectroscopy (Fig. 3).
Unfortunately, a clean NMR spectrum could not be obtained
from the reaction of substrate 6 but clean 13C NMR spectra
from substrates 7 and 8 were recorded. A solution of 7 in
HF/SbF5 provided 1H and 13C NMR spectra consistent with the
formation of the dicationic arenium–ammonium dication 9.17
Thus, it seems also reasonable to postulate the in situ formation of
Fig. 2 Schematic nucleophilic attack of intermediates A and/or B0 to
form 5- and 6-membered rings and calculated relative free energies of
the resulting Wheland intermediates E and E0.16
c
5878 Chem. Commun., 2012, 48, 5877–5879
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indoline 4 and tetrahydroquinoline 5 products. With deacti-
vated substrates, the formation of the superelectrophile B,
containing a m-hydrido bridged carbocation, could be postu-
lated. Then, B leads to the more stable (poly)cationic species E
which is the precursor of the anti-Markovnikov product.
In conclusion, we showed that an anti-Markovnikov addition
on N-allylic derivatives occurred in superacid. Moreover, during
intramolecular processes, such a reaction became completely
regioselective in the presence of strongly deactivated nucleophiles.
The selectivity of the reaction probably stemmed from the ability
to form m-hydrido bridged carbocation containing superelectro-
philic intermediates. Such an unprecedented anti-Markovnikov
addition to a non-conjugated double bond, under acidic condi-
tions, expands the possibilities for application of HF/SbF5 super-
acid chemistry to a range of strategies in organic synthesis.
Financial support from the CNRS, the University of Poitiers,
the Region Poitou-Charentes is gratefully acknowledged. We also
would like to thank Bernard Langlois for helpful discussions.
Fig. 3 Results from low-temperature 13C NMR studies of anilines in
HF/SbF5 (compared to theoretical values in ppm).15
Fig. 4 Reaction of labelled substrates in HF/SbF5.
an arenium–ammonium dication from substrate 6, though, under
these conditions, the concentration of the diprotonated species
should be very low because of a fast exchange with the mono-
protonated one, which makes it difficult to detect by the slow
NMR technique. In contrast, the reaction of the deactivated
substrate 8 in superacid was not accompanied by protonation of
the aromatic ring. Only the diprotonated species 10 was detected.
It should be noted that the observed chemical shifts fitted well with
the theoretical NMR chemical shifts calculated for such postulated
intermediates.15 These observations confirm the formation of a
dicationic intermediate, either of type D from activated substrates
or of type B0 from deactivated substrates (Fig. 1).
Notes and references
1 M. Beller, J. Seayad, A. Tillack and H. Jiao, Angew. Chem., Int. Ed.,
2004, 43, 3368 and references cited therein.
2 V. V. Markovnikov, Ann. Chem. Pharm., 1870, 153, 228.
3 For a recent example of palladium-catalyzed anti-Markovnikov
addition of allylic amine, see: R. J. DeLuca and M. S. Sigman,
J. Am. Chem. Soc., 2011, 133, 11454.
4 To the best of our knowledge the only reported examples of anti-
Markovnikov electrophilic addition on nitrogen containing deri-
vatives are conjugate additions, see for example conjugate additions
in superacid: Y. Zhang, J. Briski, Y. Zhang, R. Rendy and D. A.
Klumpp, Org. Lett., 2005, 7, 2505.
To gain further insight into the mechanism, experiments
with labelled substrates were also performed (Fig. 4). After
reaction with the superacid, substrate 10b produced a mixture of
products 4b and 5b incorporating 0% deuterium, confirming a
D/H exchange that proceeded through protonation/elimination
of the aromatic ring. In contrast, the exclusive formation of the
trideuterated tetrahydroquinoline 50h from the labelled deacti-
vated substrate 10h confirmed that the tetrahydroquinolines
resulting from deactivated systems could not arise via protonation
of the aromatic ring. To precise the mechanism underlying the
reactions of deactivated anilines, we investigated the formation of
B0-type unsymmetrical m-hydrido bridged intermediate. If this
non-classical cation is formed in superacid during the anti-
Markovnikov process, it would be expected to act as a hydride
abstracting agent and to perform, in the presence of perdeuterated
cyclohexane, an ionic hydrogenation process.18 This was con-
firmed by the formation of a g-labelled product 13.19
Taken together, these experimental observations and DFT
modelling suggest that two reaction pathways may operate,
depending on the aromatic ring substitution (Scheme 2). After
initial protonation of the nitrogen atom, (poly)cationic super-
electrophilic species of type B and/or D could be formed, depending
on the aromatic substitution. With activated substrates, the
formation of the dicationic ammonium–arenium dication D
could be favored. The latter acts as the precursor of a mixture of
5 J. C. Jacquesy, in Carbocation Chemistry, ed. G. A. Olah, John Wiley
and Sons, New York, 2004, pp. 359–376 and references cited therein.
6 S. Thibaudeau, A. Martin-Mingot, M.-P. Jouannetaud, O. Karam
and F. Zunino, Chem. Commun., 2007, 3198; F. Liu, A. Martin-
Mingot, M.-P. Jouannetaud, O. Karam and S. Thibaudeau, Org.
Biomol. Chem., 2007, 9, 4789.
7 G. A. Olah and D. A. Klumpp, Superelectrophiles and their
chemistry, John Wiley and Sons, New York, 2008.
8 Charge–charge repulsion in superelectrophiles can have unusual
effects in structure, bonding and charge distributions, please see:
D. A. Klumpp, Chem.-–Eur. J., 2008, 14, 2004.
9 T. S. Sorensen, in Stable Carbocation Chemistry, ed. G. K. S. Prakash
and P. v. R. Schleyer, Wiley, New York, 1997, pp. 75–136; H.-S. Andrei,
N. Solca and O. Dopfer, Angew. Chem., Int. Ed., 2008, 47, 395.
10 In superacid HF/SbF5, increasing the amount of SbF5 increases the
acidity strength of the media. J.-C. Culmann, M. Fauconet, R. Jost and
J. Sommer, New J. Chem., 1999, 23, 863 and references cited therein.
11 These results are in accordance with previously observed results in
superacid: F. Liu, A. Martin-Mingot, M.-P. Jouannetaud,
F. Zunino and S. Thibaudeau, Org. Lett., 2010, 12, 868.
12 C. Hansch, A. Leo and R. W. Taft, Chem. Rev., 1991, 91, 165.
13 Trifluoromethylated products were found to be unstable over silica
that could explain the low obtained yields.
14 G. A. Olah, K. K. Laali, Q. Wang and G. K. S. Prakash, Onium
ions, John Wiley and Sons, New York, 1998, pp. 280–281 for
amides and pp. 101–102 for the ether.
15 Please see ESIz for more details.
16 In this process, Hammond’s postulate allows the comparison of the rela-
tive energies of the intermediates instead of that of the transition struc-
tures. Please see: G. S. Hammond, J. Am. Chem. Soc., 1955, 77, 334.
17 A similar spectrum has been obtained by G. Olah and his group:
G. A. Olah, K. Dunne, D. P. Kelly and Y. K. Mo, J. Am. Chem.
Soc., 1972, 94, 7438.
18 K. Y. Koltunov, G. K. S. Prakash, G. Rasul and G. A. Olah,
J. Org. Chem., 2002, 67, 4330.
19 Product 11 probably comes from cyclohexane reaction (formed
after D/H exchange by s protonation of C6D12): A. Goeppert and
J. Sommer, New J. Chem., 2002, 26, 1335.
Scheme 2 Postulated reaction pathways for cyclic products formation.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 5877–5879 5879