Intramolecular hydrogen-bond activation for the addition of nucleophilic imines: 2-hydroxybenzophenone as a chemical auxiliary

Article abstract of DOI:10.1039/c8cc01479e

The addition of nucleophilic imines, using 2-hydroxybenzophenone as a chemical auxiliary, is presented. An intramolecular six-membered ring via hydrogen bonding that enhances the reactivity and selectivity is the key of this strategy, which is supported b

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Intramolecular Hydrogen-Bond Activation for the Addition of
Nucleophilic Imines: 2-Hydroxybenzophenone as Chemical
Auxiliary†‡
Received 00th January 20xx,
Accepted 00th January 20xx
Houcine Choubane,a,b Alberto F. Garrido-Castro,a Cuauhtemoc Alvarado,a Ana Martín-Somer,c
Andrea Guerrero-Corella,a Mortada Daaou,b Sergio Díaz-Tendero,c,d,e Carmen Maestro,a Alberto
Fraile,a,e and José Alemán*a,e
DOI: 10.1039/x0xx00000x
www.rsc.org/
The
addition
of
nucleophilic
imines,
using
2- oxygen makes the O-H quite acid, and under the basic medium
hydroxybenzophenone as chemical auxiliary, is presented. An in which this reaction is performed (with 20 mol% of the
intramolecular six-membered ring via hydrogen bonding that Jørgensen-Hayashi catalyst), the abstraction of the proton
enhances the reactivity and selectivity is the key of this strategy, becomes feasible, leading towards the β-addition to the
which is supported by DFT calculations and experimental trials.
iminium ion intermediate. Following derivatization, this
approach gives rapid access to enantioenriched 1,3-diols.
Remarkably, the obvious and analogue β-addition of an iminic
nitrogen to unsaturated aldehydes, which could give access to
1,3-aminoalcohols by using the corresponding imine, has not
been reported until now (middle, Scheme 1).8 We wondered if
the lack of reported work was related to the bad results
yielded by the addition of these nucleophilic species, whose
Wynberg published in 1981 the reaction between aromatic
thiols and conjugated cycloalkenones catalysed by cinchona
derivatives to afford optically active 3-arylthiocycloalkanones.1
This paper presents
a detailed investigation into the
mechanism of the catalytic asymmetric system, in which a
hydrogen bond between the catalyst’s hydroxyl group and the
enone carbonyl group, followed by deprotonation of the thiol
by the quinuclidine core, is described. It therefore represents a
landmark in bifunctional catalysis,2 wherein the key role that
hydrogen bonding plays in the catalytic system is highlighted.
In this context, other hydrogen-bond catalysts have been
developed, such as TADDOL, which has proven to be
extraordinary due to the enhancement of the acidity via
intramolecular activation of the hydroxyl group (OH···OH).
More recently in this catalytic context, different authors,
namely Takemoto,3 Krische,4 Vicario,5 and Palomo6 (top,
Scheme 1), have employed different chemical auxiliaries to
either increase the electrophilicity of amides or ketones, or
control the stereochemistry and reactivity (nitroalkenes and
aldehydes), via intramolecular hydrogen-bond activation.
In 2007, Jørgensen et al. described the addition of oximes
to aldehydes catalysed by pyrrolidine derivatives (middle,
Scheme 1).7 Interestingly, the high electronegativity of the
poor reactivity could be attributed to the low acidity of the N
H
proton compared to the OH proton (different
electronegativity). Therefore, we considered if an
intramolecular hydrogen-bond activation would facilitate the
addition to the unsaturated aldehydes, providing good
reactivity and enantioselectivity.
a
Known Catalytic Intramolecular Hydrogen-Bond Activations
O
O
O
O
H
O
H
N
H
O
R1
N
O
O
NBoc
R2
H
H
O
R1
R1
R1
R2
Takemoto (2006)
Krische (2006)
Vicario (2012)
Palomo (2014)
1,3-diols
Identification of the Limitation
b
R
O
R'
OH
N
aminocatalysis
CHO
N
+
+
R''
R''
R
R'
CHO
R''
R
R'
NH
R'
aminocatalysis
CHO
1,3-aminoalcohols
N
R
CHO
R''
not acidic
enough?
Design of a New Chemical Auxiliary
c
Acidity
Increase
Easy Recovery
After Use
OH
O
H
Inexpensive
Easy Imine Formation
High
ees
Good Yields
H
Strong
Hydrogen
Activation
O
N
Ph
b
L.S.P.B.E, Département de Chimie Organique Industrielle, Faculté de Chimie,
Université des Sciences et de la Technologie d'Oran- Mohamed Boudiaf- B.P 1505 El
Mnaouer, Oran, 31000, Algérie.
1g = 10€
C=N Bond:
Easy Hydrolysis
After Addition
c
Departamento de Química (Módulo 13), Facultad de Ciencias, Universidad
Autónoma de Madrid, 28049 Madrid, Spain.
Scheme 1. Background and strategy for the addition of imines to
unsaturated aldehydes by hydrogen-bond activation of the imine.
d
Condensed Matter Physics Center (IFIMAC), Universidad Autónoma de Madrid,
28049 Madrid, Spain.
e
Institute for Advanced Research in Chemical Sciences (IAdChem), Universidad
Autónoma de Madrid, 28049 Madrid, Spain.
‡ Electronic Supplementary Information (ESI) available: See DOI: 10.1039/x0xx00000x.
This journal is © The Royal Society of Chemistry 20xx
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Table 1. Screening of the reaction conditions for the addition of 1b to 2a.a
Consequently, we looked for a chemical auxiliary that
would feature the following characteristics: i) be recyclable; ii)
inexpensive; and iii) removable. Considering these factors, we
postulated whether 2-hydroxybenzophenone would be an
appropriate candidate, since it can form a six-membered ring
via intramolecular hydrogen bonding, and it can be easily
released after ketimine hydrolysis. In this communication, we
show how intramolecular hydrogen-bond activation is a good
strategy to enhance the reactivity while also increasing the
enantioselectivity. In addition, DFT calculations are included to
clarify the role of the hydrogen-bond activation and to find the
reasons for the noted improvements.
Entry
Catalyst (mol%)
3a (20)
Solvent
DCM
DCM
DCM
DCM
DCM
Tol
Time (h)
18
Yield (%)b
80
ee (%)c
66
1
2
3
4
5
6
7
8
9
3b (20)
18
25
25
As a proof of concept, we performed the reaction of the
commercially available 1a with the aldehyde 2a in the
presence of catalyst 3a at room temperature, followed by
condensation to afford the Wittig product 4a for analysis
purposes (equation a, Scheme 2). Under these conditions, the
reaction proceeded with low conversion (24%) and low
enantioselectivity (31% ee) after 20h. However, when the
reaction was performed with the ketimine 1b, a dramatic
change was found, noticing in this case full conversion and
80% ee after 20h without further optimization. With these
results in hand, we began to screen the reaction (Table 1) and
study the scope (Tables 2-3).
3c (20)
18
41
30
3d (20)
18
19
30
3e (20)
18
46
0
3a (20)
18
85
80
3a (20)
THF
18
66
80
3a (20)
Xylene
Tol
18
29
43
3f (20)
6
70
>99
a Reactions were performed on a 0.1 mmol scale of 1b in 0.4 mL of the indicated
solvent. b Isolated yields after flash chromatography. c Determined by chiral-SFC.
Table 2. Scope of the reaction for the addition of 1b to different aldehydes
2.a
The use of different catalysts
3 has a clear influence on the
final enantioselectivity (entries 1-5). Thus, sterically-hindered
Jørgensen-Hayashi catalysts 3a and 3b were better than
hydroxyl derivatives 3c and 3d, or thiourea catalyst 3e. With
the preliminary best catalyst in hand (3a), we studied different
solvents such as THF, xylene and toluene, with the latter one
affording the best yield and selectivity (entries 6-8). When a
bulkier catalyst featuring an OTBDMS group was used (3f), only
one enantiomer was observed. These optimal conditions
(entry 9) were employed to further the scope of the aldehyde
(Table 2) and nucleophile (Table 3).
Entry
R
Yield (%)b
70-5a
72-5b
73-5c
88-5d
93-5e
85-5f
ee (%)c
>99
>99
>99
>99
91
1
2
3
4
5
6
7
8
n-Pr
Et
n-Bu
n-Pen
n-Hex
i-Pr
>99
>99
>99
41
CH2CH2CH=CH-Et
96-5g
41-5h
47-5i
The reaction tolerates different lengths in the alkyl chain,
from ethyl to hexyl (entries 1-5), with very high
enantioselectivities (>99%), although a slightly lower value was
CO2Et
9
Ph
a
b
Reactions were performed on a 0.1 mmol scale of 1b in 0.4 mL of toluene.
Isolated yields after flash chromatography. c Determined by chiral-SFC.
attained with the hexyl group (91% ee, entry 5). The
isopropyl-substituted and olefin-containing -unsaturated
aldehydes were found to be excellent substrates for the
reaction, obtaining 5f and 5g with complete
enantioselectivities (>99%, entries 6 and 7). The inclusion of an
β-
α,β
ester in the β-position led to 5h with 99% ee (entry 8), though
diminished yield. Unfortunately, the use of an aromatic group
gave 5i with low ee, yet moderate yield (entry 9).
We then focused our attention on the use of different
ketimines (Table 3). Different substituents at the para position
with respect to the ketimine can be used, as shown by the
successful reactions performed with ketimines 1c (R’ = MeO)
and 1d (R’ = NO2; with low yield and enantioselectivity).
Substituents at the para position in relation to the hydroxyl
group were also studied. Therefore, the p-methoxy and p-
chloro substituted ketimines 1e and 1f were used, obtaining in
both cases the Wittig products 5l and 5m with good yields and
enantioselectivities. The straightforward removal of the
chemical auxiliary allowed us to convert these substrates into
some interesting products employing simple chemical
transformations (Scheme 3). For instance, the Wittig product
a
Scheme 2. Proof of concept in the reaction with ketimines 1a and 1b
Determined by 1H NMR. b Determined by chiral-SFC.
.
5a could be easily hydrolysed to obtain the δ-aminoester 6
2 | J. Name., 2012, 00, 1-3
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Table 3. Reactions of different ketimines 1 with aldehyde 2a.a
R'
H
H
O
N
HO
O
3f (20 mol%)
N
Ph
Toluene, 11-20 h, r.t.
then
Ph3P=CHCO2Me
+
R'
n-Pr
CO2Me
n-Pr
1c-f
2a
NO2
5
OMe
Cl
OMe
HO
HO
HO
HO
N
Ph
N
Ph
N
Ph
N
Ph
CO2Me
CO2Me
CO2Me
CO2Me
n-Pr
n-Pr
n-Pr
n-Pr
5j
5k
34% yield
74% ee
5l
5m
72% yield
90% ee
b
68% yield
>99% eec
37% yield
>99% ee
a
b
Reactions were performed on a 0.1 mmol scale of
1 in 0.4 mL of toluene.
Isolated yields after flash chromatography. c Determined by chiral-SFC.
Figure 1. Gibbs free energies for deprotonated ketimine and ketimine
1a (top), and deprotonated hydroxylketimine and hydroxylketimine 1b
(down). The gradient isosurfaces (s= 0.5 a.u.) are coloured on a BGR
(equation a, Scheme 3). On the other hand, the sequential
manipulations of adduct 5f (see equation b, Scheme 3) allowed
us to determine the absolute configuration of our product by
scale according to the sign(λ2)ρ over the range -0.05 to 0.05 a.u.
the deprotonated counterpart because: i) the more
electronegative oxygen atom localizes part of the total
negative charge (-0.769); and ii) the proton (+0.412) between
the two negatively charged atoms stabilizes the molecule. It is
interesting to note that when 1b is deprotonated, the proton
remains attached to the ketimine nitrogen. Nevertheless, a
strong interaction remains between the oxygen and the proton
chemical correlation. Firstly, complete hydrolysis of
α
,
β
δ
-
-
unsaturated ester 5f gave rise to its corresponding
aminoacid. Then, esterification with potassium tert-butoxide
followed by selective hydrogenation of the double bond led to
δ
-aminoester
aminoester (see ESI‡).9 The same stereochemical outcome was
assumed for the rest of compounds
7, which has been correlated with a known (R)-
5.
(blue NCI surface). The rest of ketimines 1c
behavior to 1b (see ESI‡).
-1f show a similar
In order to obtain a complementary picture of the
importance of the hydrogen-bond activation and a mechanistic
approach to the reaction, we carried out Density Functional
Theory simulations (SMD(toluene)/M06-2X/6-31++G(d,p))10 and
additional experiments. We first analysed the influence of the
hydroxyl group on the acidity of the ketimine, for which we
considered all the possible conformations of 1a and 1b before
and after deprotonation. The geometry for the most stable
structures is shown in Figure 1, including a “Non-Covalent
Interaction” analysis (NCI isosurfaces). The blue color shows
the presence of hydrogen bonds while the green surfaces
denote weak non-covalent interactions (for more details see
the ESI‡). Ketimine 1b displays an intramolecular hydrogen
bond between the hydroxyl group and the nitrogen that is
evidently absent in the 1a derivative. As expected, this
OH···NH bond makes 1b more acidic than 1a (by ~ 30
kcal/mol). The large increase in acidity is easily explained with
the charge distribution, which was computed with a Natural
Population Analysis.11 The negative charge generated in the
nitrogen atom is similar for 1a (-0.691) and 1b (-0.704).
However, the presence of the hydroxyl group stabilizes
Once we determined the structure of the deprotonated
ketimine, we evaluated the relative stability of the isomers in
the iminium formed after condensation of aldehyde 2a and
12
aminocatalyst 3b
;
in particular, the three possible rotamers
of the C-ArArOTMS group (sc-exo, sc-endo and the more stable
ap conformation, see ESI‡).13 Using the most stable structure
for each reactant, we studied the reaction pathway (see Figure
2). Since the nucleophilic attack of the most stable ketimine to
the iminium takes place from the opposite side of the bulky
part of the catalyst, we considered the three possible
orientations of 1b with respect to the ap conformation when
forming the Pre-Association Complex (PAC)14 formed between
the reactants (see ESI‡). The first and rate-limiting step
consists of the formation of the C-N bond with a very low
barrier of about 4 kcal/mol. This is followed by the exothermal
formation of a stable intermediate, wherein the hydrogen is
still covalently bonded to the nitrogen atom. In an almost
concerted way, a second step with a virtually negligible barrier
(~ 1 kcal/mol) takes place, involving a proton transfer to the
oxygen atom, thus yielding the final addition product, which is
slightly (~3 kcal/mol) more stable than the intermediate.
OH
O
HCl (10%)
In a simple picture, the complete reaction undergoes a
mechanism composed by a thermodynamic stage, which
consists of the deprotonation of the imine formation of the
PAC, followed by a kinetic step in which the new C-N bond is
formed. Therefore, the thermodynamic control of the reaction
is given by the acidity of the ketimine, and the kinetic control is
given by the addition to the iminium. The computed
mechanism indicates that the orientation of the reactants to
form the PAC is crucial for the reaction to take place; in
particular to the C-N bond formation. The positive charge of
NH2
O
(a)
+
THF
-10 to 0 °C
OH
N
O
n-Pr
O
n-Pr
O
δ-aminoester
6 (87% yield)
5a
90% yield
a) HCl (10%),
THF, 60 ºC
OH
O
NH2
O
(b)
+
OH
i-Pr
N
O
i-Pr
O
b) t-BuOK, r.t.
t-BuOH
c) H2, Pd/C, r.t.,
MeOH/EtOAc
O
δ-aminoester
7 (67% yield)
5f
88% yield
Scheme 3. Derivatizations of ketimine products 5.
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conversion decreases when the size of the halide becomes
larger, which could be explained due to the large
delocalization of the positive charge throughout the iminium,
leading to a greater interaction with bulkier anions. This
experimental result evidences the theoretical assumption of
an electrostatic interaction (between the cationic chiral pocket
and the anionic oxyanion of the ketimine), triggering formation
of the PAC and a kinetic control exerted by the C-N bond
formation once the complex is formed.
In conclusion, we have found that 2-hydroxybenzophenone
is a suitable candidate to form an intramolecular six-
membered ring via hydrogen bonding that can enhance the
reactivity of the corresponding ketimine while also increasing
the enantioselectivity in the addition to α,β-unsaturated
aldehydes.
Spanish Government (CTQ2015-64561-R, CTQ2016-76061-
P, MDM-2014-0377) and CCC-UAM are acknowledged. A. G.
thanks MINECO for Ph. D. fellowship (FPI), A. M. S. thanks CAM
for a postdoctoral contract (2016-T2/IND-1660).
Notes and references
Figure 2. Gibbs free energy profile for the addition of ketimine 1b to
aldehyde 2a catalysed by 3b. Three different orientations for the
attack of 1b to the iminium are considered. The TSs for the C-N bond
formation and H transfer in the lowest energy path are shown.
1
H. Hiemstra and H. Wynberg, J. Am. Chem. Soc. 1981, 103,
417.
2
For selected reviews, see: (a) Z. Zhang and P. R. Schreiner,
Chem. Soc. Rev. 2009, 38, 1187; (b) J. Alemán, A. Parra, H.
Jiang and K. A. Jørgensen, Chem. Eur. J. 2011, 17, 6890.
T. Inokuma, Y. Hoashi and Y. Takemoto, J. Am. Chem. Soc.
2006, 128, 9413.
the iminium ion and the negative charge of the deprotonated
ketimine suggest that the interaction between them to form
the PAC must be of electrostatic nature. To understand the
relative orientation of both reactants in the PAC, we computed
the electrostatic potential mapped on the surface of the
electron density (see bottom-right, Figure 2). The analysis of
the Molecular Electrostatic Potential (MEP) shows that the
attraction between the two molecules is purely electrostatic.
The negative area (red) of the ketimine, localised in the
nitrogen-oxygen region, interacts with the positive area of the
iminium ion. The bulky part of the catalyst prevents the
approach from the upper face, while in the bottom face, the
cationic pocket created around the C=N bond in the iminium
leads to the three possible orientations of the ketimine (green,
blue and black traces, Figure 2) of the PAC considered in the
computed mechanism. Only images of TSs of the kinetically
most favourable pathway (black trace) have been shown for
clarity (see ESI‡ for green and blue traces). To prove this
hypothesis, we performed the reaction between 1b and 2a in
the presence of tetrabutylammonium halide salts (TBAX, X =
Cl, Br, I). The positive iminium ion would interact with the
anionic halide. We found that the reaction
3
4
5
6
C. K. Jung and M. J. Krische, J. Am. Chem. Soc. 2006, 128
17051.
,
G. Talavera, E. Reyes, J. L. Vicario and L. Carrillo, Angew.
Chem. Int. Ed. 2012, 51, 4104.
E. Badiola, B. Fiser, E. Gómez-Bengoa, A. Mielgo, I. Olaizola, I.
Urruzuno, J. M. García, J. M. Odriozola, J. Razkin, M. Oiarbide
and C. Palomo, J. Am. Chem. Soc. 2014, 136, 17869.
7
8
S. Bertelsen, P. Dinér, R. L. Johansen, and K. A. Jørgensen, J.
Am. Chem. Soc. 2007, 129, 1536.
The 1,3-aminoalcohols can be obtained via nitrogen
surrogates via iminium ion, see e.g.: For Cbz or Boc-N
derivatives, see: a) Y. K. Chen, M. Yoshida and D. W. C.
MacMillan, J. Am. Chem. Soc. 2006, 128, 9328. b) I. Ibrahem,
R. Rios, J. Vesely, G.L. Zhao and A. Córdova, Chem. Commun.
2007, 849. For succinamide derivatives, see c) H. Jiang, J. B.
Nielsen, M. Nielsen and K. A. Jørgensen, Chem. Eur. J. 2007,
13, 9068. d) I. Arenas, A. Ferrali, C. Rodríguez-Escrich,
F.Bravo and M. A. Pericàs, Adv. Synth. Catal. 2017, 359
2414.
,
9
A. J. Burke, S. G. Davies, A. C. Garner, T. D. McCarthy, P. M.
Roberts, A. D. Smith, H. Rodriguez-Solla and R. J. Vickers,
Org. Biomol. Chem. 2004, 2, 1387.
10 M. J. Frisch, et al. Gaussian 09, revision B.01; Gaussian, Inc.:
Wallingford, CT, 2009.
11 A. E. Reed, L. A. Curtiss and F. Weinhold, Chem. Rev. 1988,
88, 899.
12 We considered 3b (with a similar reactivity as 3f) to reduce
the computational cost.
13 a) D. Seebach, U. Groselj, D. M. Badine, W. Bernd Schweizer
and A. K. Beck, Helvetica Chim. Acta, 2008, 91, 1999. b) Y.
Hayashi, D. Okamura, T. Yamazaki, Y. Ameda, H. Gotoh, S.
H
H
HO
O
N
3f
(20 mol%)
a
O
No TBAX
, 100% conv., >99% ee
TBAX (1 equiv.)
X = Cl, 84% conv., 88% eea
N
Ph
Ph
+
Toluene, 24 h, r.t.
then
Ph3P=CHCO2Me
n-Pr
a
CO2Me
X = Br
, 75% conv., 87% ee
n-Pr
a
X = I
, 46% conv., 92% ee
2a
1b
5a
Tsuzuki, T. Uchimaru and D. Seebach, Chem. Eur. J. 2014, 20
,
a
17077.
14 E. M. Arpa, M. Frías, C. Alvarado, J. Alemán and S. Díaz-
Tendero, J. Mol. Catal. A: Chem. 2016, 423, 308.
Scheme 4. Mechanistic tests performed under the influence of TBAX.
Conversion determined by 1H NMR and ee chiral-determined by SFC.
4 | J. Name., 2012, 00, 1-3
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