Diaminomethylenemalononitrile as a Chiral Single Hydrogen Bond Catalyst: Application to Enantioselective Conjugate Addition of α-Branched Aldehydes

Article abstract of DOI:10.1002/asia.202100487

An improved diaminomethylenemalononitrile organocatalyst, bearing a N,N-disubstituted structure, promoted enantioselective conjugate addition reaction of α-branched aldehydes with vinyl sulfone, affording adducts with excellent enantioselectivities (up to 96% ee). Mechanistic studies revealed that the diaminomethylenemalononitrile motif holds the vinyl sulfone substrate using a single hydrogen bond accompanied by multiple weak interactions, including electrostatic C?H???O interactions.

Full text of DOI:10.1002/asia.202100487

doi.org/10.1002/asia.202100487
Communication
Diaminomethylenemalononitrile as a Chiral Single Hydrogen Bond
Catalyst: Application to Enantioselective Conjugate Addition of
α-Branched Aldehydes
Masahiro Kawada, Ryo Tsuyusaki, Kosuke Nakashima, Hiroshi Akutsu, Shin-ichi Hirashima,
Takashi Matsumoto, Hikaru Yanai,* and Tsuyoshi Miura*[a]
Abstract: An improved diaminomethylenemalononitrile
organocatalyst, bearing a N,N-disubstituted structure, pro-
moted enantioselective conjugate addition reaction of α-
branched aldehydes with vinyl sulfone, affording adducts
with excellent enantioselectivities (up to 96% ee). Mecha-
nistic studies
revealed
that
the
diaminometh-
ylenemalononitrile motif holds the vinyl sulfone substrate
using a single hydrogen bond accompanied by multiple
weak interactions, including electrostatic CÀ H···O interac-
tions.
In molecular recognition and supramolecular chemistry, hydro-
gen bond (H-bond) and non-covalent interactions, including a
CÀ H···O interaction, are key factors for the host-guest
complexation.[1] Although each non-covalent interaction is not
strong, it makes the complex favorable in multiple bonding
conditions. The organocatalyst attracted attention in the past
decades because of its advantages, including environmentally
benign properties, high stereo- and chemo-selectivities, and
easy handling.[2] N,N’-Disubstituted thioureas,[3] squaramides[4]
are privileged structural motifs for several enantioselective
molecular transformations. H-bond catalysts bearing two NÀ H
moieties serve as double H-bond donors, yielding a character-
istic complexation with reaction substrates, which is essential to
attain excellent enantioselectivity, as well as reasonable cata-
lytic activity. In our ongoing project, which focuses on
developing organocatalysts bearing novel H-bond donor moi-
Figure 1. (A) Structures of typical bifunctional H-bond catalysts and their
catalytic mechanism. (B) Previous DMM-catalyzed conjugate addition
reaction.
similar to thiourea/squaramide motifs. However, in some
reactions, DMM-derived catalysts exhibited better stereoselec-
tivities than the corresponding thiourea/squaramide-derived
catalysts.[7] To understand the differences in such structurally
related catalysts, we have reinvestigated a relationship between
the molecular structure of DMM-derived catalysts and the
catalytic activity. Herein, we report N,N,N’-trisubstituted DMM
derivatives, where the third substituent is introduced to one
nitrogen atom, still catalyze the reaction in an enantioselective
manner. In addition, a careful screening of the substituent helps
in the development of an improved DMM catalyst, which
caused better enantioselectivity compared with the reported
organocatalysts, including our DMM catalyst 1.[5,8] Experimental
and theoretical analyses of this reaction have shown the
importance of multiple non-covalent interactions, including the
CÀ H···O interaction between enamine-bounding catalyst mole-
cule and vinyl sulfone substrate.
ety, an organocatalyst
1
bearing N,N’-disubstituted
diaminomethylenemalononitrile (DMM) structure instead of
thiourea/squaramide motif has been found (Figure 1A). This
catalyst shows excellent properties in enantioselective conju-
gate addition reactions of α-branched aldehydes with vinyl
sulfones (Figure 1B).[5] We reported DMM-catalyzed aldol and
other conjugate addition chemistry.[6–7]
We speculated that the two NÀ H moieties in the N,N’-
disubstituted DMM motif serve as a double H-bond donor
[a] Dr. M. Kawada, Mr. R. Tsuyusaki, Dr. K. Nakashima, Dr. H. Akutsu, Dr. S.-
i. Hirashima, Prof. T. Matsumoto, Dr. H. Yanai, Prof. T. Miura
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences
1432-1 Horinouchi, Hachioji, Tokyo 192-0392 (Japan)
E-mail: yanai@toyaku.ac.jp
This research began from an unexpected result in rescreen-
ing of the DMM-derived organocatalysts in enantioselective
conjugate addition of α-branched aldehydes to a vinyl sulfone
(Scheme 1): the reaction of racemic 2-phenylpropanal rac-2a
with (PhSO2)2C=CH2 3a in the presence of N,N-dibenzyl DMM
tmiura@toyaku.ac.jp
Supporting information for this article is available on the WWW under
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Scheme 1. Screening of DMM Catalysts.
Scheme 2. Enantioselective Conjugate Addition Reaction Using 5a.
catalyst 5a gave the adduct 4a with better enantioselectivity
than that by N-monobenzyl DMM catalyst 1[5] (89% ee for 1 vs.
96% ee for 5a). Although this reaction has been used as a kind
of touchstone for primary amine organocatalysts,[8] the highest
enantiomer excess has been achieved in this case. This
observation was a surprise because the N,N-disubstitution in
the DMM catalyst 5a was contradictory to the conventional
transition state model using double H-bonding with the sulfone
substrate. The electronic behavior of pendant benzyl groups
affected the enantioselectivity. The replacement of (3,5-bis
(trifluoromethyl)phenyl)methyl groups with simple benzyl and
(4-methoxyphenyl)methyl groups resulted in a decrease in the
enantioselectivity (82% ee for 6, 80% ee for 7). Considering that
a C–D···X interaction is weaker than the corresponding CÀ H···X
interaction,[9] we examined the reaction in the presence of a
catalyst [D]4-5a in which benzylic positions of DMM catalyst 5a
were deuterated. Although the reaction occurred, the enantio-
selectivity dropped to 93% ee. Benzylic deuteration of the first-
Figure 2. (A) A linear correlation between enantiomer excesses of catalyst
5a (eeCAT) and product 4a (eeP). (B) Proposed catalyst cycle for the improved
DMM catalyzed reaction.
mechanism catalyzed by primary amines,[8] this reaction should
include a catalytic cycle as shown in Figure 2B. TFA-mediated
dehydrative condensation between the DMM catalyst 5 and
aldehyde 2 produces a reactive enamine intermediate INT-1. In
addition, the C–C bond-forming step with vinyl sulfone 3
produces iminium species INT-2, and its hydrolysis causes the
formation of product 4 along with the regeneration of DMM
catalyst 5. Among each step, the CÀ C bond-forming step would
be a rate/enantioselectivity-determining step.[12]
We conducted the density functional theory (DFT) simu-
lation [PCM(CH2Cl2)-M06-2X/6-31+G(d) level of theory] of the
reaction of 2-phenylpropanal 2a with a vinyl sulfone 3b (R3 =
Me) (Figure 2B). Here a catalyst 5b in which one of the (3,5-bis
(trifluoromethyl)phenyl)methyl groups in 5a was replaced with
a simple methyl group (R=Me) was adopted as a model. After
many attempts (for detailed reaction profiles, see the ESI),
transition state TS-S with the E-enamine structure and its Z-
isomeric transition state TS-R were found as energetically
acceptable transition states (Figures 3A–C). Here, the participa-
tion of TFA in the transition states are not considered.[13]
Transition state TS-S gives experimentally obtained major
generation DMM catalyst
1
caused impairing of the
enantioselectivity.[10]
With the improved DMM catalyst 5a, the reactions of some
α-branched aldehydes 2 were examined (Scheme 2). Aldehydes
2b–d bearing p-substituted phenyl groups reacted with 3a to
afford the corresponding adducts 4b–d in good yields with
enhanced enantioselectivities. Although m-bromophenyl alde-
hyde 2e was a problematic substrate in the reaction with the
first-generation catalyst 1, the enantioselectivity was increased
to 95% ee using the improved catalyst 5a. Moreover, aldehyde
2f bearing 2-naphthyl group was converted to the product 4f
with 94% ee.[11]
To obtain mechanistic insights of the reaction catalyzed by
improved DMM catalyst 5a, we evaluated a correlation of
enantiomer excess of product 4a (eeP) toward that of the DMM
catalyst 5a (eeCAT). As shown in Figure 2A, a good linear
relationship was observed. This fact proved that one catalyst
molecule participates in the enantioselectivity-determining
transition state of the reaction. Considering the reported
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Figure 3. (A) Line-bond projections of TS-S and TS-R. Sulfur-oxygen bonds are drawn as charge-separated resonance structure because of their pronounced
single covalent bond character.[18] (B) Ball-stick projection of TS-S. (C) Ball-stick projection of TS-R. (D) QTAIM bond paths. BCPs are shown by green small
spheres. (E) Strong N1À H1···O2LP1 NBO interaction, and (F) Weak C3À H3···O2LP2 NBO interaction.
enantiomer and it was preferable than TS-R (ΔΔG� =
2.7 kcalmolÀ 1 at 298 K).
the push-pull Cα-Cβ bond in the catalyst molecule (Figure 4)
should be noted. Two covalent-bond indices, Natural Localized
Molecular Orbital (NLMO)/Natural Population Analysis (NPA)
bond order and delocalization index (DI) are 1.27 and 1.15,
respectively. The highly charge-separated character of this
partial double bond is supported as follows: 1) NPA charges of
Cα (À 0.51 e) and Cβ (+0.57 e), and 2) highly twisted geometry
around CαÀ Cβ bond axis in TS-S.[18] Consequently, the relatively
heavy contribution of the charge-separated resonance structure
II in this push-pull system[19] enhances C3À H3···O2 interaction,
as well as N1À H1···O2 bonding.[20,21] Relatively large E(2) value of
the N1À H1···O2 interaction plays a central role in stabilizing the
transition state complex. Therefore, we conclude that the N,N-
dibenzyl DMM motif serves as a single H-bond donor. Despite
weak stabilization by each CÀ H···O interaction, their cooperation
assists to construct the suitable asymmetric reaction field, which
is required for the highly enantioselective CÀ C bond formation.
Such a DMM motif would favor the molecular design of tailor-
made H-bond catalysts.
The Bader’s Quantum Theory of Atoms In Molecules
(QTAIM) analysis,[14] which represents the chemical bond by the
bond path defined by an electron density function between
atoms, visualizes the interatomic interactions in TS-S (Fig-
ure 3D). Here, two bond paths for the NÀ H···O interaction
(N1À H1···O2 and N2-H2···O1) are found. In addition, the sulfonic
oxygen atoms interact with three hydrogen atoms in enamine-
bounding catalyst, including H3 on benzylic C3, H4 on aromatic
C4, and H5 on C5 in the cyclohexane backbone.[15] The QTAIM
parameters of N1À H1···O2 interaction, such as electron density
2
(1BCP) and Laplacian (r 1BCP) at the bond critical point (BCP),
imply that the bond may be classified into common H-bond
2
(1BCP =0.0211 ebohrÀ 3; r 1BCP = +0.0691 ebohrÀ 5).[16] However,
2
1BCP (0.0131 ebohrÀ 3) and r 1BCP (+0.0468 ebohrÀ 5) in
N2À H2···O1 interaction are notably reduced. In all CÀ H···O
interactions, QTAIM parameters confirmed the importance of
electrostatic factor (for more details, see the ESI). This
conclusion is consistent with the Natural Bond Orbital (NBO)
analysis[17] which is used as an orbital-based bond descriptor
linked to the Lewis structure (Figures 3E and 3F). The sum of
the second perturbation energies [E(2)] in N1À H1···O2 inter-
action is much larger than that in N2À H2···O1 interaction
(11.7 kcalmolÀ 1 vs. 2.6 kcalmolÀ 1). Moreover, E(2) values in four
CÀ H···O interactions are similar in magnitude to the weak
N2À H2···O1 interaction (2.2 kcalmolÀ 1 for C3À H3···O2,
1.9 kcalmolÀ 1 for C4À H4···O2, 2.2 kcalmolÀ 1 for C5À H5···O2, and
3.1 kcalmolÀ 1 for C5À H5···O3). A clear single bond character of
In conclusion, we successfully developed N,N-dibenzyl DMM
organocatalyst 5a for the enantio-selective conjugate addition
Figure 4. Resonance structures in the push-pull system.
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Nakashima, H. Akutsu, T. Sakai, Y. Matsushima, M. Kawada, T. Miura, Org.
Lett. 2021, 23, 480.
reaction of α-branched aldehydes with vinyl sulfone. Compared
with previous reports, the new DMM catalyst realized higher
enantioselectivity. The DFT calculation revealed that the N,N-
dibenzyl DMM motif served as a single H-bond donor, but the
transition states were secondary stabilized by multiple non-
covalent interactions, including the CÀ H···O interaction. Push-
pull effects in the DMM backbone are key factors for enhancing
such weak interactions. Currently, the developments of novel
organocatalysts bearing the N,N-dialkyl DMM motif and applica-
tions to other asymmetric reactions are being investigated in
our laboratory.
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Acknowledgements
This work was supported in part by JSPS KAKENHI Grant Number
20K06948.
[11] The reaction of 4a in a synthetic scale was shown in the SI.
[12] When enantiomerically enriched 4a (92% ee) was treated for 24 h at
room temperature by 10 mol% of rac-5a in the presence of rac-2a and
TFA, 4a was recovered in 99% without significant loss of ee (91% ee)
(See: the SI). This result supports that the retro-reaction giving rise to a
racemic product is negligible under the present conditions.
Conflict of Interest
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The authors declare no conflict of interest.
Keywords: organocatalyst
·
multiple interactions
· vinyl
sulfone · conjugate addition · hydrogen bond
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Manuscript received: May 6, 2021
Revised manuscript received: June 22, 2021
Accepted manuscript online: July 2, 2021
Version of record online: ■■■, ■■■■
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COMMUNICATION
Dr. M. Kawada, Mr. R. Tsuyusaki,
Dr. K. Nakashima, Dr. H. Akutsu,
Dr. S.-i. Hirashima, Prof. T.
Matsumoto, Dr. H. Yanai*, Prof. T.
Miura*
A novel organocatalyst using single
hydrogen-bond and multiple non-
covalent interactions (including
CÀ H···O interactions) effectively
promoted asymmetric conjugate
additions of α-branched aldehydes to
vinyl sulfone, affording the addition
products with excellent enantioselec-
tivities (up to 96% ee).
1 – 5
Diaminomethylenemalononitrile
as a Chiral Single Hydrogen Bond
Catalyst: Application to Enantiose-
lective Conjugate Addition of α-
Branched Aldehydes