Enantioselective aza Michael-type addition to alkenyl benzimidazoles catalyzed by a chiral phosphoric acid

Article abstract of DOI:10.1002/anie.201508231

Highly enantioselective Michael-type addition (MTA) reactions between N-protected alkenyl benzimidazoles and either pyrazoles or indazoles as nitrogen nucleophiles are accomplished for the first time using chiral phosphoric acid catalyst. Theoretical studies elucidated the reaction pathway and the origin of the stereochemical outcomes, where the catalyst substituent and the N-protecting group of benzimidazole contributed to the resulting high enantioselectivity. Heterocycle squared: Highly enantioselective Michael-type addition reactions to alkenyl benzimidazoles with pyrazoles and indazoles as nitrogen nucleophiles are accomplished using a chiral phosphoric acid catalyst. Theoretical studies elucidated the reaction pathway and the origin of the stereochemical outcome. The catalyst substituent and the N-protecting group (PG) of the benzimidazole contribute to the resulting high enantioselectivity.

Full text of DOI:10.1002/anie.201508231

Angewandte
Communications
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International Edition: DOI: 10.1002/anie.201508231
German Edition: DOI: 10.1002/ange.201508231
Organocatalysis
Enantioselective Aza Michael-Type Addition to Alkenyl
Benzimidazoles Catalyzed by a Chiral Phosphoric Acid
Ya-Yi Wang, Kyohei Kanomata, Toshinobu Korenaga, and Masahiro Terada*
Abstract: Highly enantioselective Michael-type addition
MTA) reactions between N-protected alkenyl benzimidazoles
challenge. In fact, they have been used in dearomatization
processes such as the catalytic asymmetric hydrogenation of
(
[
7]
and either pyrazoles or indazoles as nitrogen nucleophiles are
accomplished for the first time using chiral phosphoric acid
catalyst. Theoretical studies elucidated the reaction pathway
and the origin of the stereochemical outcomes, where the
catalyst substituent and the N-protecting group of benzimid-
azole contributed to the resulting high enantioselectivity.
heteroarenes, in which an endocyclic double bond under-
goes nucleophilic addition in an enantioselective fashion.
However the LUMO-decreasing activation of a double bond
attached to the azaarene, which enables 1,4-conjugate addi-
tion to alkenyl azaarenes, has not yet been realized using
chiral phosphoric acids. The proposed transformation has an
intrinsic problem associated with the conformational flexi-
bility of the acyclic system, where control of the newly
generated stereogenic center is rather difficult. Our project is
focused on the development of enantioselective Michael-type
addition (MTA) to alkenyl azaarenes catalyzed by a chiral
phosphoric acid (1; Figure 1a).
T
he construction of aromatic N-heterocyclic motifs bearing
complex side chains, particularly chiral ones in an enantio-
enriched form, is of paramount significance and great interest
in the synthetic community because they are ubiquitously
found in natural products and biologically active compounds
(
e.g., pharmaceutical substances and agrochemicals). These
structures are commonly constructed by forming N-hetero-
[
1]
cycles using chiral precursors. Another synthetic method-
ology, the direct enantioselective functionalization of prochi-
ral heterocyclic compounds, is an attractive alternative
strategy in terms of its atom and step economy. An ideal
example of this type of construction is the conjugate addition
to an alkenyl moiety, having an electron-deficient aromatic N-
heterocycle (azaarene), a reaction which is an analogue of the
classical Michael addition to an a,b-unsaturated carbonyl
compound. This particular transformation is often seen in
[2]
biosynthesis, and has also been developed by synthetic
[
3]
chemists into a beneficial synthetic method. However,
asymmetric conjugate addition to alkenyl azaarenes has
[
4]
been less exploited and remains a challenging task.
Indeed, to promote these processes, harsh reaction conditions
are usually required because energetically less favorable
intermediates are generated through a transient dearomati-
zation step.
[
5]
Chiral phosphoric acids have emerged as versatile
[6]
catalysts for various enantioselective transformations, and
thus have the potential of meeting the aforementioned
[
*] Y.-Y. Wang, Dr. K. Kanomata, Prof. Dr. M. Terada
Department of Chemistry, Graduate School of Science
Tohoku University
Figure 1. a) Enantioselective MTAs to alkenyl azaarene catalyzed by
chiral phosphoric acid. b) The aza MTA between either pyrazoles or
indazoles and alkenyl N-protected benzimidazoles.
Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
E-mail: mterada@m.tohoku.ac.jp
Homepage: http://www.orgreact.sakura.ne.jp/index.html
To validate the transformation envisaged, we employed
benzimidazole as the aromatic N-heterocyclic unit for the
alkenyl azaarene. While many five- or six-membered aro-
matic N-heterocycles (e.g., thiazole, pyridine, and pyrimidine)
have been reported as basal units of the alkenyl azaarenes for
Michael-type additions, the alkenyl benzimidazoles 2 (Fig-
ure 1b) have never been used in the proposed MTA, despite
benzimidazoles being typical elements of biologically active
Prof. Dr. M. Terada
Research and Analytical Center for Giant Molecules, Graduate School
of Science, Tohoku University, Sendai 980-8578 (Japan)
Prof. Dr. T. Korenaga
Department of Chemistry and Bioengineering, Graduate School of
Engineering, Iwate University, Morioka 020–8551 (Japan)
[3]
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201508231.
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[
8]
compounds. The reactivity of 2 as well as the stereochemical
outcome of the addition products could be tuned through the
choice in the protecting group at the nitrogen atom of the
benzimidazole moiety. A further consideration is the type of
nucleophile employed. By taking account of the synthetic
importance of CÀN bond formation as well as the potential
mixture was obtained when using 2b. Considering the
favorable reactivity and stereochemical outcome using 2c,
we employed EWG-protected benzimidazoles (2) in the
following studies.
To enhance the ee value of the product 4c, we thoroughly
[10]
screened the reaction conditions. As shown in Table 1, 1b,
having a 9-anthryl group at the 3,3’-positions, exhibited better
ee values than that of 1a (entry 4 versus 3). THF was the best
of the solvents screened for the reaction of 2c when using 1b,
utility of the addition products, we selected pyrazoles (3) and
[
9]
indazoles (5) as nitrogen nucleophiles to establish the
reaction system. Herein, we report the development of an aza
MTA between either 3 or 5 and the N-protected 2, catalyzed
by 1. The reaction is an efficient method for coupling two
aromatic N-heterocycles, which are potential pharmaco-
phores or ligands, into one molecule (Figure 1b).
At the outset of our studies, the reaction of the pyrazole
a with a series of alkenyl benzimidazoles (2) was inves-
tigated (Table 1). These reactions were performed using the
[11]
thus giving rise to 4c in 82% ee (entries 4–6). It is unusual
that a higher ee value was achieved in the more polar THF
than in the less polar CH Cl or toluene, which have been
2
2
commonly used in chiral phosphoric acid catalyzed reactions.
The temperature effect was next explored. Lowering the
temperature to À408C dramatically improved the ee value
(98% ee), and a long reaction time ensured a good yield.
Delightfully, the reactions of 2d and 2e, which are protected
by other common EWGs (Cbz and Ts, respectively), also gave
similarly excellent ee values, and the result using 2e (Ts
protected) was slightly better than the others (entries 7–9).
The Ts group of the addition product 4e could be readily
removed in accordance with a known procedure, affording
deprotected products without any loss of the enantiomeric
3
[
a]
Table 1: Optimization of the reaction conditions.
[12]
purity.
Hence N-Ts-protected benzimidazoles were
employed for further investigations.
[
b]
[c]
Entry 2 (PG)
1
Reaction conditions
4
Yield [%]
ee [%]
With the optimal reaction conditions in hand, the scope of
the present transformation was demonstrated in the reaction
between a series of N-protected benzimidazoles (2) and either
pyrazoles (3) or indazoles (5). The results are summarized in
Table 2. For some less reactive substrates, higher temper-
atures and longer reaction times were required to ensure
acceptable yields (T: temperature, t: time). The electron-
donating dimethyl substituent on the benzimidazole ring of 2
did not compromise the ee value of 4 f. The absolute config-
uration of 4 f was determined to be S by single-crystal X-ray
diffraction analysis. The higher temperature was required
for the reaction of the electron-withdrawing chloro-substi-
tuted benzimidazole because of the solubility of the substrate
in THF, and resulted in a slight reduction of the ee value of 4g.
Further investigations showed that different alkyl substituents
attached to the vinyl terminus of 2 led to excellent enantio-
selectivities (4h–l), irrespective of the substituent. Never-
theless, a phenyl group was an unsuitable substituent given
the low yield and ee value observed with 4m. Intriguingly,
introducing an ester group to vinyl terminus of 2 led to the
addition reaction at the a-position of the ester functionality,
thus affording 4n in moderate ee value. This result indicates
that EWG-protected benzimidazole greatly polarizes the
C=C bond rather than the carbonyl group under the influence
1
2
3
4
5
6
7
8
9
2a (H)
1a CHCl , 258C, 48 h
4a
<5
95
99
99
99
99
99
99
96
–
2
3
2b (Bn) 1a CH Cl , 258C, 48 h 4b
2c (Boc) 1a CH Cl , 258C, 18 h 4c
2c
2c
2c
2c
2
2
51
73
78
82
98
98
99
2
2
1b CH Cl , 258C, 18 h 4c
2 2
1b toluene, 258C, 18 h 4c
1b THF, 258C, 18 h
1b THF, À408C, 48 h
4c
4c
4d
4e
[
[
[
d]
d]
d]
[e]
[e]
[e]
2d (Cbz) 1b THF, À408C, 48 h
2e (Ts)
1b THF, À408C, 48 h
[
1
a] Unless otherwise noted, reactions were carried out with (R)-
(0.01 mmol), 2 (0.1 mmol), and 3a (0.1 mmol) in 1.0 mL of the
indicated solvent (0.1m). [b] Determined by H NMR analysis of the
crude reaction mixture using CH Br as the internal standard. [c] Deter-
mined by chiral stationary phase HPLC analysis. [d] With (R)-1b
0.02 mmol), 2 (0.2 mmol), and 3a (0.2 mmol) in 1.0 mL THF (0.2m).
e] Yield of isolated product. PG=protecting group, THF=tetrahydro-
[13]
1
2
2
(
[
furan, Ts =4-toluenesulfonyl.
chiral phosphoric acid catalyst 1a (10 mol%) at room
temperature. The reaction of the unprotected 2a did not
proceed under these reaction conditions (entry 1). In contrast,
substrates protected by either an electron-donating group
EDG) or an electron-withdrawing group (EWG) afforded
the desired addition products in excellent yield (entries 2 and
). Of particular interest is that the reaction of the N-tert-
butoxycarbonyl (Boc)-protected 2c was faster than that of N-
benzyl (Bn)-protected 2b. The more basic 2b would be
protonated at the nitrogen atom more strongly by 1a,
however the less-basic 2c, which has a higher electrophilicity
than 2b, exhibited the higher reactivity. These results suggest
that the inherent electrophilicity of 2 is the dominant factor
governing the reactivity, rather than the basicity at the
nitrogen atom of 2. More interestingly, moderate enantio-
meric excess (ee) was observed in 2c, while an almost racemic
(
3
of the phosphoric acid, and hence functions as a strong
directing group. The alkenyl azarene bearing an imidazole,
instead of benzimidazole, is also an applicable substrate,
albeit leading to the addition product in moderate yield and
[14]
ee value.
The scope with respect to the nucleophiles, 3 and 5, was
further investigated (Table 2). Varying the substituent at the
C4-position of 3 was tolerated (4o, 4p, 4q) and both the
electron-withdrawing bromide (4r) and electron-donating
methyl (4t) worked well at the C3-position. In contrast,
9
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[
a]
Table 2: Scope with respect to substrates.
through the energetically less favorable process of a transient
dearomatization step. These findings prompted us to study
further the mechanism of this intriguing transformation. We
therefore conducted computational analysis to acquire mech-
anistic insights into the present reaction. The catalyst 1b, 2e,
and 3a were used for the theoretical studies and all
[15]
calculations were performed with the Gaussian 09 package.
The geometries of transition states were fully optimized and
characterized using frequency calculations at the B3LYP
[16]
density-functional theory with the 6-31G* basis set. Rela-
tive Gibbs free energies were obtained by single-point energy
calculations of the optimized structures at the M06-2X/6-
[
17]
3
7
1G* level with the SCRF method based on CPCM (e =
[18]
.4257 for THF)
followed by the addition of thermal
corrections which were calculated at the geometrical opti-
[19]
mization by B3LYP/6–31G* level.
Three-dimensional (3D) transition structures of the
stereodetermining CÀN bond-forming step are illustrated in
[20]
Figure 2. The transition-state TS-s [affords (S)-4e] is more
À1
stable than TS-r [affords (R)-4e] by 4.4 kcalmol at the
À1
B3LYP/6-31G* level (1.5 kcalmol for the free energy) using
the catalyst (R)-1b, and is consistent with the experimental
[
a] Unless otherwise specified, reactions were carried out with (R)-1b
(
(
0.02 mmol), 2 (0.2 mmol), and either 3 or 5 (0.2 mmol) in 1.0 mL THF
0.2 m) at À408C for 48 h. If other conditions (T, t) were used see data
within parentheses. Yields of isolated products are given. The ee value
was determined by chiral stationary phase HPLC analysis. [b] No
N2 adducts were observed in these cases. [c] Combined yield of two
1
regioisomers. [d] Determined by H NMR analysis of the crude reaction
mixture.
introduction of a sterically hindered phenyl group at the C3-
position led to a marked decrease in the ee value of 4s.
Furthermore, the formation of two regioisomers, N1 and
N2 adducts, would be expected, when using C3-substituted
pyrazoles. 3-Methylpyrazole underwent the reaction at the N1
and N2 positions to afford a regioisomers 4ta and 4tb in 6:1
mixture, however in the reactions of 3-bromo- and 3-phenyl-
pyrazole, the N1-adducts 4r and 4s were formed exclusively.
3
,5-Dimethyl-substituted pyrazole is also applicable, despite
showing a slight decrease in yield and ee value of 4u. Finally,
the indazole 5 was employed as a nucleophile and the
corresponding products 6 were obtained in good yields with
high enantio- and regioselectivities, although the ee value of
the minor product 6ab was only moderate.
The present aza MTA to alkenyl benzimidazole exhibited
extremely high enantioselectivity in most cases. In addition, it
can be considered that the products 4 and 6 were formed
Figure 2. 3D structures of the transition states a) TS-s and b) TS-r.
À1
Relative energies at the B3LYP/6-31G* level are shown in kcalmol
.
À1
Relative Gibbs free energies (in kcalmol ) at the CPCM (THF)/M06-
[19]
2X/6-31G* level are shown within parentheses.
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results. Further structural analysis of TS-s and TS-r allowed
identification of the major factors contributing to the efficient
enantioselection. In both transition structures, 2e and 3a
interact with the chiral phosphoric acid 1b through two
hydrogen bonds. Furthermore, the alkenyl moiety and the
benzimidazole core of 2e lie in the same plane. This coplanar
fragment is almost parallel to the anthryl plane of the catalyst
substituent to avoid steric congestion in the energetically
more-favorable TS-s (Figure 2a). In contrast, in the less
favorable TS-r, the coplanar fragment is inserted perpendic-
ularly between two anthryl planes (Figure 2b), in which the
methyl group of the alkenyl moiety and the tail-end of the
benzimidazole core are located close to the top and bottom
anthryl substituents. This arrangement leads to steric repul-
sion between the substrate and the catalyst (dashed red circles
in Figure 2b), which would destabilize TS-r. More interest-
ingly, to avoid steric repulsion between the alkenyl moiety of
In conclusion, we accomplished the first enantioselective
aza MTA of pyrazoles and indazoles to alkenyl benzimida-
zoles using a chiral phosphoric acid catalyst. The reaction
affords the corresponding products with both benzimidazole
and pyrazole (indazole) units, which are ubiquitous elements
of biomolecules and pharmacophores, in excellent enantio-
selectivities in most cases. Theoretical calculations elucidated
the origin of the stereochemical outcomes and the reaction
pathway. Structural analysis of the transition states at the CÀ
N bond-forming step revealed that not only the catalyst
substituent but also the N-protective group of benzimidazole
contributed to the resulting high enantioselectivity. More-
over, the energy profile formulated by the theoretical studies
indicates that the reaction proceeds through a transient
dearomatization process. Further studies on the development
of enantioselective transformations using other types of
alkenyl azaarenes and nucleophiles are underway in our
laboratory.
2
e and the N-Ts group, the alkenyl moiety is oriented to the
opposite side of the N-Ts group. In addition, this conforma-
tion would be further stabilized by the intramolecular
CÀH···O hydrogen bond between the a-vinyl proton and the Acknowledgments
oxygen atom of the sulfonamide moiety (dashed red lines in
[
21]
Figure 2). In fact, the distances between the a-vinyl proton
and the oxygen atom (2.27 Š in TS-s, 2.22 Š in TS-r) are
considerably shorter than the sum of the van der Waals radii
of hydrogen and oxygen atoms (ca. 2.7 Š). The observed high
enantioselectivity also stems from the conformational fixation
of the alkenyl moiety by the Ts group.
This work was partially supported by a Grant-in-Aid for
Scientific Research on Innovative Areas “Advanced Molec-
ular Transformations by Organocatalysts” from MEXT,
Japan. We also thank the Japan Society for the Promotion
of Sciences for the JSPS Resarch Fellowship for Young
Scientists (K.K.).
[22]
As illustrated in Figure 3, the reaction energy profile
shows that the intermediate complex CP2, consisting of the
initial product INTand (R)-1b, forms prior to the product 4e.
CP2 is energetically comparable to CP1 which is the
precursor of the CÀN bond-forming step. However subse-
Keywords: enantioselectivity · heterocycles · Michael additions ·
organocatalysis · synthetic methods
How to cite: Angew. Chem. Int. Ed. 2016, 55, 927–931
Angew. Chem. 2016, 128, 939–943
quent energetically favorable rearomatization of INT via TS-
rearom suppresses the retro-aza Michael-type reaction to
CP1. The rearomatization is accomplished through tautome-
rization of the exo double bond of INT aided by the chiral
phosphoric acid 1b, which eventually yields the thermody-
namically more stable product 4e.
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are shown in kcalmol
.
9
30
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[
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À
21] The intermolecular C H···O hydrogen bond is formed between
the b-vinyl proton of 2e and the oxygen atom of the phosphate
moiety (dashed red lines in Figure 2). The distances between the
b-vinyl proton and the oxygen atom are 2.19 Š and 2.18 Š in TS-
s and TS-r, respectively.
[
[
[
10] See the Supporting Information for further information on the
screening of reaction conditions.
11] The reaction of (Z)-2c (Boc) with 3a in THF at 258C for 36 h
afforded 4c in 49% yield with 10% ee.
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of other products were assigned by analogy.
[
22] See the Supporting Information for the 3D structures of CP1,
CP2, TS-rearom, and 4e/(R)-1b.
[
Received: September 2, 2015
Revised: November 8, 2015
Published online: December 7, 2015
Angew. Chem. Int. Ed. 2016, 55, 927 –931
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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