Bronsted acid catalyzed asymmetric SN2-Type O-alkylations

Article abstract of DOI:10.1002/anie.201209983

Bridging the gap: Bronsted acids catalyze an intramolecular S _N2-type alkylation of alcohols with ethers by bridging a pentacoordinate transition state, thus simultaneously activating both the leaving group and nucleophile (see scheme). Density functional calculations provide detailed insight into the course of the reaction and the transition-state structure.

Full text of DOI:10.1002/anie.201209983

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DOI: 10.1002/anie.201209983
Asymmetric Organocatalysis
Brønsted Acid Catalyzed Asymmetric SN2-Type O-Alkylations**
ˇ
´
Ilija Coric, Ji Hye Kim, Tjøstil Vlaar, Mahendra Patil, Walter Thiel, and Benjamin List*
Asymmetric Brønsted acid catalysis has flourished in recent
years especially in the context of nucleophilic additions to
carbon-based electrophiles.[1] These reactions generally
involve the formal approach of nucleophiles at the p* orbital
of an sp2-hybridized carbon atom of electrophiles, typically
imines, but also aldehydes, ketones, or certain Michael
acceptors.[2] In contrast, substitution reactions involving
nucleophilic attack at the s* orbital of an sp3-hybridized
carbon atom are underexplored in this context. The bifunc-
tional nature of chiral phosphoric acids could offer unique
opportunities for catalyzing such reactions. We hypothesized
that these acids could bridge the trigonal bipyramidal
transition state of an SN2 reaction, to simultaneously activate
both the leaving group and the nucleophile.[3]
though previously unprecedented and much more challenging
asymmetric transetherification reaction.[9]
For the initial studies we selected ethyl benzhydryl ether
as substrate and (S)-TRIP (1) as catalyst (Table 1, entry 1).[10]
The benzhydryl ether was chosen as it was expected to be
Table 1: Reaction development.
Entry
R
T
Conv. [%][a]
e.r. (3a)[b]
1
2
3
4
5
Et
H
408C
RT
408C
408C
408C
26
32
35
29
49
81:19
63:37
iPr
(iPr)2CH
tBu (2a)
87.5:12.5
73.5:26.5
93.5:6.5
(s=37)
89:11
The proposed activation mode could potentially enable
access to a large group of SN2-type alkylation reactions.
Asymmetric Brønsted acid catalysis has already been success-
fully applied to various alkylation reactions that proceed
through an SN1-type mechanism,[4] but the analogous SN2
reactions are rare.[5–7] Herein, we describe the development of
Brønsted acid catalyzed asymmetric SN2-type O-alkylation
reactions employing benzylic ethers as electrophiles. We show
that the phosphoric acid TRIP catalyzes highly enantioselec-
tive intramolecular transetherification reactions of hydroxy
ethers resulting in an efficient kinetic resolution.
6[c]
tBu (2a)
508C
56
(s=33)
[a] Determined by 1H NMR analysis or calculated from ee values of the
product and the recovered starting material. [b] Determined by HPLC
analysis on a chiral stationary phase. [c] 5 mol% of the catalyst, PhCl as
the solvent, without molecular sieves (M.S.).
a good substrate for either SN2- or SN1-type reactions.[11]
Indeed, the reaction proceeded at a slightly elevated temper-
ature with 20 mol% of the catalyst and furnished 1,3-
dihydroisobenzofuran 3a with moderate enantioselectivity
(Table 1, entry 1). When free alcohol was used instead of the
ethyl ether, the enantioselectivity dropped sharply (Table 1,
entry 2). However, an increase in the steric bulk of the leaving
group to iso-propyl ether had a positive impact on the
selectivity (Table 1, entry 3). These results suggested that the
leaving group is involved in the enantiodetermining step of
the reaction. Encouraged by this observation, we prepared
substrate with a bulky (iPr)2CH group (Table 1, entry 4).
However, the enantioselectivity was decreased in comparison
to the iPr substituted ether. Gratifyingly, by using tert-butyl
ether 2a, product 3a could be obtained with a high enantio-
meric ratio of 93.5:6.5 at 49% conversion (Table 1, entry 5).
Interestingly, substrate 2a also exhibited a significantly higher
reactivity compared to the other ether substrates. Examining
the remaining starting material revealed that a kinetic
resolution had taken place. The e.r. of recovered ether (S)-
Encouraged by our recent discovery that chiral phospho-
ric acids are able to activate an acetal moiety,[8] we hoped that
Brønsted acids of this type could potentially also activate the
relatively unreactive ether groups and catalyze an analogous
ˇ
´
[*] I. Coric, J. H. Kim, T. Vlaar, Dr. M. Patil, Prof. Dr. W. Thiel,
Prof. Dr. B. List
Max-Planck-Institut fꢀr Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 Mꢀlheim an der Ruhr (Germany)
E-mail: list@kofo.mpg.de
[**] We gratefully acknowledge generous support from the Max Planck
Society. J.H.K. is thankful to the National Research Foundation of
Korea for an internship fellowship and T.V. is grateful for an Erasmus
scholarship. We thank H. Schucht and Dr. R. Goddard for crystal
structure analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201209983.
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Table 2: TRIP-catalyzed asymmetric benzylation of alcohols.
2a was 91.5:8.5, corresponding to a selectivity factor (s) of 37,
where the selectivity factor= (rate of fast-reacting enantio-
mer)/(rate of slow-reacting enantiomer). Further optimiza-
tion enabled us to use only 5 mol% of the catalyst while
retaining high selectivity (Table 1, entry 6).
Having optimized the reaction conditions we explored the
generality of the transformation (Table 2). We were partic-
ularly interested in applying the reaction to less-reactive
substrates. As expected, removing the electron-donating
methoxy group from the substrate had a negative effect on
the reaction rate and selectivity (Table 2, entry 2). At 808C,
product 3b could be obtained with a moderate selectivity
factor of 8. However, kinetic resolution employing tertiary
alcohols proceeded with an exceptional enantioselectivity
giving selectivity factors of 142 and 179 (Table 2, entries 3 and
4). Notably, the tertiary alcohol substrates exhibited signifi-
cantly higher reactivity than primary alcohol rac-2b. Chloro-
substituted substrate rac-2e gave a similarly high enantiose-
lectivity, albeit the reaction was slightly slower (Table 2,
entry 5). The combination of a tertiary alcohol nucleophile
and an electron-rich aromatic system resulted in a superb
kinetic resolution with a selectivity factor greater than 500,
which is similar to the values obtained for enzyme-catalyzed
reactions (Table 2, entry 6). Encouraged by these results, we
next explored simpler substrates that lack the aromatic tether.
Gratifyingly, the reaction of ether rac-2g proceeded with
a selectivity factor of 44 at 508C (Table 2, entry 7). The
reaction of the isomeric ortho-methoxy-substituted benzyl
ether rac-2h proceeded with a selectivity factor of 25 although
a significantly higher temperature of 808C was necessary
(Table 2, entry 8). With the simple unsubstituted benzyl ether
rac-2i, an even higher temperature of 1208C was required.
Remarkably, the reaction still proceeded with good selectivity
(Table 2, entry 9). Tertiary alcohols rac-2j and rac-2k under-
went the transetherification reaction at the same temperature
with impressive selectivity factors of 82 and 58 (Table 2,
entries 10 and 11). Such excellent enantioselectivity is rarely
encountered in Brønsted acid catalysis at high tempera-
tures,[2,12,13] therefore suggesting the reaction has a well-
organized transition state.
Entry
1
T [8C]
(t [h])
Conv.
[%][a]
Product
s
50
(22)
56
42
50
33
80
(46)
2
3
8
60
(16)
142
60
(16)
4
51
179
60
(25)
5
6
48
51
161
570
20
(10)
50
(24)
7
8
50
43
44
25
80
(21)
Heteroaryls can also be used in our alkylation reaction.
Bisheterocycle 3l could be readily obtained with a selectivity
factor of 36 (Table 2, entry 12). Our transetherification
reaction is particularly suitable for obtaining biologically
relevant[14] 2-substituted tetrahydrofurans, such as 3g–i and
3l, as the starting alcohols can be easily obtained from the
corresponding (hetero)aryl bromides [Eq. (1); see the Sup-
porting Information].[15]
120
(22)
9
48
47
16
82
120
(22)
10
120
(24)
11
12
53
49
58
36
40
(70)
The absolute configurations of product 3i and of the
recovered enantioenriched 2i were determined to be (R) by
comparison of the optical rotation with literature data and
with an authentic sample made by an alternative synthesis,
respectively (see the Supporting Information). A single
crystal X-ray analysis of compound (S)-3 f confirmed that
benzene tethered substrates show the same sense of enan-
[a] Calculated from ee values of the product and the recovered starting
material.
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tioinduction (see the Supporting Information, Figure S1). The
absolute configurations of other products were assigned by
analogy.
The fact that the reaction proceeds with an inversion of
the configuration of the secondary benzyl stereocenter is
consistent with an SN2-type mechanism. The strong influence
of the leaving group (Table 1) and the alcohol nucleophile
(Table 2, entries 2–4 and 9–11) on the reaction enantioselec-
tivity indicates that both are involved in the transition state,
which further corroborates an SN2-type reaction. In accord-
ance with an SN2 mechanism, stereospecific inversion also
occurred when an enantioenriched starting material was
treated with an achiral Brønsted acid [Eq. (2)].[16] Trans-
Figure 1. B3LYP/6-31G* optimized structure of the SN2-type transition
À
À
state leading to (R)-3i. Selected distances (ꢁ): O2 H1 1.72, O2 H2
À
À
À
2.17, O3 H3 1.69, C1 O1 2.50, C1 O4 2.19.
etherification of ether (S)-2d catalyzed by diphenyl phos-
phoric acid furnished tetracycle (R)-3d, demonstrating that
neither the product nor the starting material racemize to
a significant extent during the reaction. In addition, the
participation of an SN1-type pathway that would lead to loss
of enantiomeric purity of the product could be excluded.
The reaction mechanism of the TRIP-catalyzed intra-
molecular alkylation of 2i (Table 2, entry 9) was further
studied using density functional theory. Geometry optimiza-
tions and intrinsic reaction coordinate (IRC) calculations
were performed at the B3LYP/6-31G* level. Single-point
calculations at the gas-phase optimized geometries were
carried out with larger basis sets (6-31 + G**) and with
inclusion of continuum solvation and empirical dispersion
corrections to arrive at more accurate energetics. The
Supporting Information contains details on the applied
computational methods and the numerical results
(Tables S1–S4) as well as additional computational data on
other pathways considered (Scheme S1 and Figure S2).
Rewardingly, our initial predictions were indeed con-
firmed by theory showing the Brønsted acid to act as
a bifunctional activator bridging the pentacoordinate tran-
sition state. For substrate 2i, the barrier to nucleophilic
substitution through the SN1-type pathway was found to be
significantly higher than the barrier to cyclization through the
SN2-type pathway. In the lowest-energy transition state for the
SN2-type substitution reaction (Figure 1), the leaving group is
activated by proton transfer from the catalyst, the alcohol
nucleophile is activated by hydrogen bonding to the Brønsted
basic oxygen atom of the catalyst, and there is an additional
stabilizing interaction between the catalyst and the hydrogen
atom (H2) on the reacting carbon atom. The reaction profile
along the IRC path resembles a classic SN2 process (Figure 2)
accompanied by two proton transfers.
Figure 2. Energy and selected distances along the intrinsic reaction
coordinate. For atom designations see Figure 1.
nucleophile (at O1). This theoretical scenario is in accordance
with the experimentally observed increase in reactivity of the
starting ethers in the order: tBu > iPr> Et (Table 1, entries 1,
3, and 5), with more electron-rich ethers favoring the initial
protonation event. The transition state for (S)-3i was found to
be 2.4 kcalmolÀ1 higher in free energy than the transition
The catalyst initially protonates the leaving group (at O4)
to facilitate its later departure, the actual substitution (at C1)
with the synchronous formation and splitting of bonds occurs
in the transition state region of the IRC path, and in the final
stage of the reaction, the catalyst recovers a proton from the
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J. Am. Chem. Soc. 2007, 129, 12084; b) G. L. Hamilton, T. Kanai,
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tally determined selectivity factor.[17] A highly organized SN2-
type transition state, such as that shown in Figure 1, can be
regarded as the origin of the excellent enantioselectivity
observed even at 1208C (Table 2).
In summary, we demonstrate a novel mode of activation
with chiral Brønsted acid catalysts that formally involves
nucleophilic attack at the s* orbital of saturated carbon
electrophiles. Phosphoric acids were shown to catalyze an
intramolecular asymmetric SN2-type alkylation reaction of
alcohols with racemic secondary benzylic ethers to result in
a catalytic asymmetric transetherification reaction. The very
high selectivity observed even at 1208C, demonstrates the
potential of asymmetric Brønsted acid catalysis for the
activation of normally unreactive functional groups such as
ethers and potentially other less reactive substrates. The
generality of the new SN2 activation mode reported here is
currently under investigation.
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Received: December 13, 2012
Published online: February 10, 2013
Keywords: alkylation · asymmetric catalysis ·
.
nucleophilic substitution · organocatalysis · transetherification
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