Axial-Chiral Biisoquinoline N, N′-Dioxides Bearing Polar Aromatic C-H Bonds as Catalysts in Sakurai-Hosomi-Denmark Allylation

Article abstract of DOI:10.1021/acs.orglett.8b02457

The design, synthesis, and evaluation of axial-chiral biisoquinolines bearing polar aromatic C-H bonds as Lewis base catalysts are reported. Lewis bases containing the 3,5-bis(trifluoromethyl)phenyl group were found to be significantly more enantioselecti

Full text of DOI:10.1021/acs.orglett.8b02457

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Axial-Chiral Biisoquinoline N,N′‑Dioxides Bearing Polar Aromatic
C‑H Bonds as Catalysts in Sakurai-Hosomi-Denmark Allylation
Carlyn Reep,† Pierpaolo Morgante,†,‡ Roberto Peverati,*,†,‡ and Norito Takenaka*,†
‡
†Department of Biomedical and Chemical Engineering and Sciences, and Theoretical and Computational Chemistry, Florida
Institute of Technology, Melbourne, Florida 32901, United States
S
* Supporting Information
ABSTRACT: The design, synthesis, and evaluation of axial-chiral
biisoquinolines bearing polar aromatic C-H bonds as Lewis base
catalysts are reported. Lewis bases containing the 3,5-bis-
(trifluoromethyl)phenyl group were found to be significantly
more enantioselective for a wider range of substrates than those
bearing aromatic residues that are not strongly electron-deficient in
the allylation of aldehydes with allyltrichlorosilane. Also, optically
pure 3,3′-dibromo-1,1′-biisoquinoline N,N′-dioxide that has not
been previously reported was synthesized as a common catalyst precursor to facilitate the study.
ypervalent silicon complexes generated from chiral Lewis
base catalysts and chlorosilanes (LSiCl3, L = H, Cl, alkyl,
H
enolates, etc.) are very reactive intermediates and continue to be
an important source for the development of new enantio-
selective synthetic methods.1 Reported examples include
reduction of imines and ketones (L = H),2 chlorination of
epoxides (L = Cl),3 alkylation of carbonyls (L = allyl, etc.),4,5 and
aldol reactions (L = enolates).5 Also, it was established that
chiral Lewis bases bind SiCl4 to generate in situ powerful Lewis
acids for the activation of electrophiles.6 This field of catalysis
research is largely triggered and driven by the seminal and
leading studies of Denmark et al.1 Significant contributions also
1
̌
́
include those from Kocovsky, Malkov, and Nakajima.
Regarding the stereochemical aspects of these transformations,
the ligand configuration of such a hypervalent silicon complex is
considered to play a central role for the enantioselectivity of a
reaction because the relative orientation of a chiral catalyst and
reacting substrates in the enantioselectivity-determining tran-
sition state largely depends on it.2−7 For example, a C2
symmetric bidentate Lewis base, LSiCl3, and an electrophile
can produce five diastereomeric complexes that have different
enantioselectivities (Figure 1a). Currently, the trans-Cl complex
is thought to form preferentially based on the stereoelectronic
theories.7f,g,i On the other hand, the recent computational
studies regarding alkylation of aldehydes disclosed by Wheeler
et al. support arrangements with cis chlorines.7a,b,d,e This cis
model is based on stabilizing electrostatic interactions among
ligands that were characterized by DFT calculations (e.g.,
stabilizing interaction between a formyl H and a Cl on Si). Even
with these notable advances made, however, the control of such
ligand configurations remains largely elusive and significantly
challenging. In this context, we envisioned a strategy to
selectively generate the trans-Cl complex by the internal H-
bonding from the catalyst (Figure 1b).8 In this scenario, not only
the trans-Cl complex could be selectively generated over the
other diastereomeric complexes but also the expected complex
Figure 1. Catalyst design. (a) Five possible diastereomeric
hexacoordinate complexes of a bidentate catalyst, LSiCl3 and an
electrophile. (b) Internal H-bonding concept and design of
corresponding catalysts.
adopts a Λ-cis-α structure9 by virtue of H-bonding in which
chirality is at the Si atom (the reaction center) and its two
coordination sites for L and E are identical (two C2 symmetric
sites). Thus, high enantioselectivity could be expected from such
a structure. Herein we introduce a new concept to enhance the
stereoselectivity in Lewis base catalysis of chlorosilane-mediated
reactions.
Received: August 1, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02457
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
With the aforementioned idea in hand, some of the attributes
that we deemed to be important for our initial catalyst design are
the following; (1) a scaffold should be C2 symmetric and rigid to
minimize the number of possible complexes, (2) H-bond donors
such as alcohols and amides should be avoided because these
have Lewis basic lone pairs that might form extra dative bonds to
chlorosilanes (i.e., undesired aggregations), and (3) H-bond
donor units should be easily tuned to facilitate the study. On the
basis of these criteria, an axial-chiral biisoquinoline motif bearing
polar aromatic C-H bond donors at its 3, 3′-positions appeared
to be a suitable starting point. It should be mentioned that this
kind of axial-chiral Lewis base catalyst bearing aromatic residues
that are not strongly electron-deficient at the corresponding
positions is reported in the literature.10
While the H-bond donor ability of the ortho-CH bonds of the
3,5-bis(trifluoromethyl)phenyl group11,12 was clearly demon-
strated by Schreiner et al. and transition-metal-bound chlorines
are reported to accept H-bonds,13 the extent to which peripheral
Cl atoms of a hypervalent chlorosilane could accept H-bonds
cannot be easily discerned without computational analysis.14 As
such, we began our study by performing a preliminary energy
minimization of a neutral complex of 1a (Scheme 1) and SiCl4 in
dioxides containing aromatic residues at their 3,3′-positions.10
However, these catalysts either take 11 steps to make10c or
require that the 3,3′-aromatic groups must be introduced in the
first step of their syntheses, and optical resolution of each
aromatic variant must be addressed individually.10a,b On the
other hand, 1,1′-biisoquinoline N,N′-dioxide is readily accessed
in optically pure form on gram scale in just three steps from
commercially available isoquinoline,18 although the functional-
ization of its 3,3′-position is reported to be nontrivial.19
Therefore, we decided to pursue a possibility that the protocol
we previously developed for the corresponding functionalization
of helicene-derived pyridine N-oxides20 would work on 3.18 To
our delight, it provided desired (S)-3,3′-dibromo-1,1′-
biisoquinoline N,N′-dioxide (2a) in 86% yield, which under-
went the Suzuki coupling without loss of enantiopurity. Notably,
this step (tuning of steric and electronic properties of catalysts)
is the last step in our synthesis.21 It is worth mentioning that
given the privileged use of the pyridine N-oxide group in
asymmetric catalysis,1,22 2a is expected to be of general interest
to chemists in the fields of catalysis, synthesis, drug discovery,
etc., just like 3,3′-dibromo-BINOL.21
Allylation of aldehydes with allyltrichlorosilane23 catalyzed by
chiral Lewis bases17,24 (a.k.a. Sakurai-Hosomi-Denmark allyla-
tion24c) has been a testing ground for new chiral Lewis bases
(Table 1).4 We chose 4-methoxybenzaldehyde for an initial
a
Scheme 1. Synthesis of Lewis Base Catalysts
a
Table 1. Evaluation of Catalysts
entry
catalyst
4, R =
yield (%)
er
98:2
98:2
a
The conventional Suzuki coupling protocols were used without
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
2a
1a
1b
1d
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
(E)-PhCHCH
(E)-PhCHCH
(E)-PhCHCH
87
83
81
86
96
83
0
71
68
62
further optimization. See Supporting Information (SI) for details.
95.5:4.5
97.5:2.5
the gas phase with the B97-D exchange-correlation functional15
and the 6-31G* basis set.16 The result shows that the distances
between the distal Cl atoms and the relevant H atoms on the 3,5-
bis(trifluoromethyl)phenyl groups are 2.4 Å (Figure 2),
b
6:94
91:9
95:5
88.5:11.5
84.5:15.5
10
a
Reactions were performed with aldehyde (1.0 mmol), (S)-catalyst
(0.1 mol %), allyltrichlorosilane (1.2 equiv), and N,N-diisopropyl-
ethylamine (3.0 equiv) in 1.0 mL of solvents (1.0 M in
MeCN:EtCN26 = 3:1). Yields are those of chromatographically
purified compounds. The er values were determined by HPLC
b
analysis; see the SI for details. (R)-1e was used.
Figure 2. A preliminary structure of the neutral (S)-1a·SiCl4 complex in
the gas phase.
model substrate because a huge range of enantioselectivities for
its allylation was reported with structurally related catalysts.25
To our delight, 1a provided the product in 87% yield with 98:2
er. The catalyst with 3,4,5-trifluorophenyl group (1b) was
equally effective. The catalysts with less electron-deficient Ar
units (1c,e,f) were found to be clearly less selective except for
3,5-dimethylphenyl substituted catalyst 1d. Strangely, 3,3′-
dibromo-1,1′-biisoquinoline N,N′-dioxide (2a) did not catalyze
the reaction. Next, we evaluated the three best catalysts
identified (1a,b,d) for structurally distinct cinnamaldehyde
(Table 1, entries 8−10) because a similar catalyst10c was
reported to give the corresponding product in 69% ee. The
catalyst bearing 3,5-bis(trifluoromethyl)phenyl unit (1a) was
found to be significantly more selective than the other two
confirming the possible formation of two distal H-bonding
interactions. While the magnitude and nature of electrostatic
interactions between the catalyst and Cl atoms will substantially
change upon ionization (i.e., formation of cationic hypervalent
silicon complexes by the dissociation of a chloride anion), we
interpreted this result as support for our internal H-bonding
concept at this point and proceeded to synthesize the
corresponding catalysts.
Inspired by Nakajima’s landmark report17 that introduced
1,1′-biisoquinoline N,N′-dioxide (3) as a Lewis base catalyst,
̌
́
Hayashi, Kocovsky, Malkov, and Kotora independently
developed the axial-chiral biisoquinoline (or bipyridine) N,N′-
B
DOI: 10.1021/acs.orglett.8b02457
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
catalysts, identifying it as an optimum catalyst among those
evaluated.
provided products in substantially higher yields with no effect on
enantioselectivity (6h−k). As such, we evaluated its activity on
our model aldehyde and found that 1g provided the product 6a
in 71% yield in only 2.5 h with essentially the same selectivity,
which corresponds to the turnover frequency of 568/h.
Strangely enough, the product of thiophene-2-carbaldehyde
(6p) appeared to inhibit the catalyst turnover (0.5 mol %
loading was needed to complete the reaction), but that of 2-
furaldehyde did not (6q). On the other hand, er of 6p was found
to be significantly higher than that of 6q. Notably, 1a effectively
catalyzed the allylation of highly functionalized 1-acetyl-3-
indolecarboxaldehyde and α-bromocinnamaldehyde despite the
fact that these aldehydes were not soluble under the reaction
condition even with twice as much solvent (0.5 M). Hydro-
cinnamaldehyde (i.e., aliphatic aldehyde) did not provide the
product, as is often the case for Sakurai-Hosomi-Denmark
allylation, presumably due to the formation of an α-chloro silyl
ether as reported by Denmark.29
Given that 1a and 1d provided the similar results for 4-
methoxybenzaldehyde while 1a was much more enantioselective
than 1d for cinnamaldehyde (Table 1), the extent to which the
3,5-bis(trifluoromethyl)phenyl group influenced the outcome of
these reactions was not so clear. Therefore, we evaluated 1d for
4-chlorobenzaldehyde, 1-naphthylaldehyde, and thiophene-2-
carbaldehyde which are different from 4-methoxybenzaldehyde
in terms of electronic, steric, and structure, respectively (Scheme
2, footnote h). Catalyst 1d provided the corresponding products
(6g, 6m, and 6p) in similar yields but in substantially lower
enantioselectivities (89:11, 94:6, and 84:16 er, respectively). It is
interesting to note that 1d has the essentially same chiral pocket
as Hayashi’s best bipyridine catalyst which contains a 4-
methoxy-3,5-dimethyl phenyl group at the corresponding
positions,10c and substrate scopes of these two catalysts were
found very similar (i.e., only highly enantioselective for 4-
alkoxybenzaldehydes). We also performed a preliminary energy
minimization of a neutral complex of 1d and SiCl4 in the same
manner and found that its ortho-CH bonds do not H-bond to
chlorines as strongly as 1a (the corresponding distance is 2.8 Å,
see Figure S2, SI). These results are consistent with the
hypothesis that H-bonding interactions provided by 1a
substantially contributed to the overall energies of accessible
diastereomeric transition states (Figure 1) favoring the trans-Cl
arrangement. On the other hand, the fact that the behavior of 1d
is largely substrate-dependent may be attributable to possible
electrostatic interaction between a formyl H and a Cl on Si that
could be an important factor to determine the accessible
transition states in the absence of sufficient electrostatic
interactions from the catalyst.7a,b,d,e
Because enantio-enriched homoallylic alcohols are indispen-
sable for the synthesis of therapeutic agents and natural
products, a plethora of allylation methodologies has been
developed over the last several decades.27 However, it still
remains an important problem for the allylation of aldehydes
that a relatively large amount of the catalyst is required for a
reasonable reaction rate in most cases (even with metal
catalysts). Highly enantioselective catalysts that work at the
0.1 mol % loading or less are extremely rare.10b−e,28 Hayashi’s
catalyst10c−e was the first example of such catalysts (state-of-the-
art in terms of the catalyst loading), but it is only highly
enantioselective for 4-alkoxybenzaldehydes and 3,4-dimethox-
ybenzaldehyde (94% and 98% ee, respectively). Therefore, the
substrate scope investigation of 1a was warranted. Overall, good
to excellent levels of enantioselectivities were observed for a
range of synthetically useful substrates (Scheme 2). Electron-
rich aldehydes were generally excellent substrates for 1a, but
halogen-substituted benzaldehydes were found to be not only
less selective but also less reactive. Because electron-rich Lewis
base catalysts are often more reactive in chlorosilane-mediated
reactions, we prepared 1g for those substrates. To our delight, 1g
a
Scheme 2. Substrate Scope
In summary, we have introduced Lewis base catalysts with C-
H bond donors as a new and highly generalizable concept in the
Lewis base catalysis. This strategy led to the discovery of highly
enantioselective Lewis bases that work at 0.05 mol % catalyst
loading for a synthetically useful substrate scope for the first
time. The detailed mechanistic investigation is underway, with
which we hope to shed light on the stereochemical mode of this
transformation. Also, we developed the practical synthesis of
optically pure 3,3′-dibromo-1,1′-biisoquinoline N,N′-dioxide 2a
that is expected to be of general interest to chemists. Further
applications of this concept and the catalysts are currently being
developed in our laboratory and will be reported in due course.
a
Reactions were performed with aldehyde (1.0 mmol), catalyst (0.05
mol %), allyltrichlorosilane (1.5 equiv), and N,N-diisopropylethyl-
amine (4.5 equiv) in 1.0 mL of solvents (1.0 M in MeCN:THF26
=
3:1). Yields are those of chromatographically purified compounds.
The er values were determined by HPLC analysis; see SI for details.
(a) Catalyst 1g. (b) 2.5 h. (c) NMR yield. (d) 0.5 mol % of 1a. (e)
0.5 M concentration. (f) 71 h. (g) 0.1 mol % of 1a. (h) Catalyst 1d
(see Scheme 1).
C
DOI: 10.1021/acs.orglett.8b02457
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(9) Narcis, M. J.; Takenaka, N. Eur. J. Org. Chem. 2014, 21.
(10) (a) Malkov, A. V.; Westwater, M.-M.; Gutnov, A.; Ramírez-
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b02457.
■
S
́
̌
́
̌
́
Lopez, P.; Friscourt, F.; Kadlcíkova, A.; Hodacova, J.; Rankovic, Z.;
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Kotora, M.; Kocovsky, P. Tetrahedron 2008, 64, 11335. (b) Hrdina, R.;
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́
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Dracínsky, M.; Valterova, I.; Hodacova, J.; Císarova, I.; Kotora, M. Adv.
Synth. Catal. 2008, 350, 1449. (c) Kina, A.; Shimada, T.; Hayashi, T.
Adv. Synth. Catal. 2004, 346, 1169. (d) Shimada, T.; Kina, A.; Hayashi,
T. J. Org. Chem. 2003, 68, 6329. (e) Shimada, T.; Kina, A.; Ikeda, S.;
Hayashi, T. Org. Lett. 2002, 4, 2799.
Experimental procedures and detailed characterization
data of all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
(11) Lippert, K. M.; Hof, K.; Gerbig, D.; Ley, D.; Hausmann, H.;
Guenther, S.; Schreiner, P. R. Eur. J. Org. Chem. 2012, 5919 and
references cited therein.
(12) Two terpene-derived pyridine N-oxides bearing 3,5-bis(CF3)Ph
group are reported. For the adverse effect of 3,5-bis(CF3)Ph group on
the allylation, see refs 7c and 12b: (a) O’Hora, P. S.; Incerti-Pradillos, C.
A.; Kabeshov, M. A.; Shipilovskikh, S. A.; Rubtsov, A. E.; Elsegood, M.
■
*N.T.: E-mail, ntakenaka@fit.edu.
*R.P.: E-mail, rpeverati@fit.edu.
ORCID
Norito Takenaka: 0000-0003-3542-1086
Notes
̌
́
R. J.; Malkov, A. V. Chem. - Eur. J. 2015, 21, 4551. (b) Kocovsky, P.;
Malkov, A. V. Pure Appl. Chem. 2008, 80, 953.
́
(13) (a) Aullon, G.; Bellamy, D.; Brammer, L.; Bruton, E. A.; Orpen,
The authors declare no competing financial interest.
A. G. Chem. Commun. 1998, 653. (b) Yap, G. P. A.; Rheingold, A. L.;
Das, P.; Crabtree, R. H. Inorg. Chem. 1995, 34, 3474.
(14) The recent computational studies by Wheeler et al. reported
stabilizing electrostatic interactions between formyl C-H and Cl-Si
within the cationic octahedral complexes. See refs 7a, b, d, e.
(15) Grimme, S. J. Comput. Chem. 2006, 27, 1787.
ACKNOWLEDGMENTS
■
We thank the National Science Foundation (CHE1461196) and
the Florida Institute of Technology for financial support of this
work.
(16) (a) Francl, M. M.; Pietro, W. J.; Hehre, W. J.; Binkley, J. S.;
Gordon, M. S.; DeFrees, D. J.; Pople, J. A. J. Chem. Phys. 1982, 77, 3654.
(b) Hariharan, P. C.; Pople, J. A. Theor. Chim. Acta 1973, 28, 213.
(17) Nakajima, M.; Saito, M.; Shiro, M.; Hashimoto, S. J. Am. Chem.
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