Controlling the C(sp3)-C(sp2) Axial Conformation in the Enantioselective Friedel-Crafts-Type Alkylation of β-Naphthols with Inden-1-ones

Article abstract of DOI:10.1021/acs.orglett.7b03415

The Friedel-Crafts-type reaction between properly functionalized inden-1-ones and 2-naphthols generates a hindered single bond which displays a unique preference for an antiperiplanar conformational diastereoisomer. The steric hindrance and the presence of an enantioenriched stereogenic center control the distribution of the two diastereomeric conformers at equilibrium and increase the energy for the rotation of the C(sp³)-C(sp²) single bond.

Full text of DOI:10.1021/acs.orglett.7b03415

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Controlling the C(sp3)−C(sp2) Axial Conformation in the
Enantioselective Friedel−Crafts-Type Alkylation of β‑Naphthols with
Inden-1-ones
Nicola Di Iorio, Giacomo Filippini, Andrea Mazzanti, Paolo Righi, and Giorgio Bencivenni*
Department of Industrial Chemistry “Toso Montanari”, Alma Mater Studiorum-University of Bologna, Viale del Risorgimento 4,
40136 Bologna, Italy
S
* Supporting Information
ABSTRACT: The Friedel−Crafts-type reaction between
properly functionalized inden-1-ones and 2-naphthols gen-
erates a hindered single bond which displays a unique
preference for an antiperiplanar conformational diaster-
eoisomer. The steric hindrance and the presence of an
enantioenriched stereogenic center control the distribution of
the two diastereomeric conformers at equilibrium and increase
the energy for the rotation of the C(sp3)−C(sp2) single bond.
meric conformers by an enantioselective transformation. The
tropisomers are compounds that have a stereogenic axis
Aalong a single bond with a hindered rotation. By tradition, new stereogenic center exerts the thermodynamic control on
the conformation of the adjacent stereogenic axis by means of
steric interactions. Finally, the installation of a large substituent
increases the rotational energy of the stereogenic axis and fixes
the configuration stability over time. The removal of the chiral
inductor releases an enantioenriched mixture of atropisomers.4
During our previous study on the asymmetric Friedel−Crafts
(F−C) alkylation of β-naphthol (2a) with inden-1-one (1a), we
obtained the enantioenriched product 3aa as a 69:31
equilibrium mixture of two diastereomeric conformers ap-3aa
and sp-3aa due to a slow rotation around the new C(sp3)−
C(sp2) bond (Scheme 2).5
the minimum energy barrier required to have a stable
stereogenic axis is 96 kJ/mol at 300 K, thus ensuring a t1/2 of
racemization of 15 min.1 The steric hindrance that surrounds
the stereogenic axis is fundamental to provide the conforma-
tional stability. Atroposelective syntheses are realized with
different methods such as dynamic kinetic resolution (DKR),
desymmetrization, coupling, and arene-forming reactions.2
Enantioenriched atropisomers, in particular, nonbiaryl
atropisomers, can also be obtained under thermodynamic
control over two equilibrating conformational diastereoisomers
(Scheme 1).3 This strategy consists of a synthetic sequence
wherein a compound with an unstable stereogenic axis is
converted into a mixture of enantiomerically pure diastereo-
Scheme 2. Asymmetric Friedel−Crafts-Type Alkylation
Scheme 1. Example of Thermodynamic Resolution
From NMR experiments, we assigned the antiperiplanar
conformation to the major conformer ap-3aa with the C3H
directed toward the naphthol peri-hydrogen and the synper-
iplanar conformation to the minor conformer sp-3aa with the
C3H directed toward the OH group of naphthol. The energy
barrier to rotation of the C(sp3)−C(sp2) stereogenic axis
(ΔGe⧧pi) for the ap-3aa to sp-3aa interconversion was
determined to be 74.5 kJ/mol by means of dynamic NMR
Received: November 1, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03415
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
experiments. In light of this equilibrium, we speculated on the
possibility of synthesizing a single enantiomerically enriched
conformational diastereoisomer through thermodynamic con-
trol over a C(sp3)−C(sp2) stereogenic axis conformation. We
rationalized that large substituents at C(8) of the naphthol and
at C(4) of the indanone together with the presence of a
stereogenic center directly bonded to the stereogenic axis could
enhance the gap between the ground-state energies of the two
conformers giving access to a single enantiomerically enriched
diastereoisomeric conformer (Scheme 3).
Table 1. Effect of the Steric Hindrance
d
e
e
,f
entry
R
R1
ap/sp
ΔG⧧epi(exp)
ΔG⧧epi (calc)
Scheme 3. Strategic Plan for the Construction of C(sp3)−
3aa
3ab
3ba
3bb
H
H
69:31
90:10
86:14
100:0
74.5
g
C(sp2) Conformational Diastereoisomers
H
NHBoc
H
83.7
72.7
79.0
Br
Br
92.1
n.d.
NHBoc
105.5
a
Reactions performed using 0.2 mmol of 1 and 0.22 mmol of 2 in 1
b
c
mL of toluene. Isolated yield. Determined by chiral HPLC analysis.
d
e
Determined by 1H NMR of the crude mixture. In kJ/mol.
f
g
Calculated via DFT at the B3LYP/6-31G(d) level. Determined on
the corresponding acetylated 4ab via 1D-EXY experiment.
tivity.8 Since we observed a partial degradation of the F−C
products 3, they were acetylated in situ immediately after the
reaction to the corresponding compounds 4. The scope of the
F−C-type reaction was explored (Table 2). All of the reactions
gave exclusively the ap-conformer with elevated enantioselec-
tivity. Different 8-substituted-β-naphthols 2b−j were reacted in
combination with 4-bromoindenone 1b. The isolated yields
ranged from moderate to very good and the enantioselectivity
was very high except for compounds ap-4bb and ap-4bc with
NHBoc and NHCbz substituents. The presence of electron-
withdrawing (Br, Cl, I) and -releasing groups (OMe, tert-
butyldimethylsilyloxy) was well tolerated and indanones ap-
4bd−bh were obtained with high enantiocontrol. β-Naphthols
with aromatic substituents gave the desired products ap-4bi
and ap-4bj with good yields and excellent ee’s.
The reactivity of new inden-1-ones 1c−e was investigated.
Remarkably, electron-deficient 1c and electron-rich derivatives
1d and 1e could be reacted with a variety of β-naphthols, giving
successful results on the corresponding indanones ap-4cf−dc.
Only 1e was scarcely reactive. However, the desired product
ap-4ed was obtained with a high ee. Interestingly, in the case of
ap-4bj and ap-4cj a 56:44 mixture of conformers revealed the
presence of a slow rotation of the C(sp2)−C(sp2) bond
connecting naphthol with an m-tolyl substituent. We prepared
β-naphthol 2k bearing a phenanthryl substituent. The reaction
with 1b gave the desired compound in 15% yield as a 1:1
mixture of ap-(R,M)-4bk and ap-(R,P)-4bk diastereoisomers
in a 94% and 65% ee, respectively. ap-(R,M)-4bk was isolated
by preparative HPLC, and a ΔG⧧epi of 125.2 kJ/mol was
measured for the rotation of the aryl−aryl bond. The R
absolute configuration was assigned to compounds ap-4bc and
ap-4bf and the S to compound ent-ap-4bd by means of single-
crystal X-ray diffraction analyses.
Furthermore, the larger steric hindrance should increase the
barrier to rotation of the single bond, thus yielding
atropisomers. This would be important because C(sp3)−C(sp2)
atropisomers are well-known,6 but their catalytic enantiose-
lective synthesis has never been reported.
We set out to replace the hydrogen atoms with bulkier
groups at either the β-naphthol or inden-1-one and then in
both partners and measure the barrier for the ap- to sp-
interconversion. The reactions were performed using a 20 mol
% of 9-amino-9-deoxy-epi-quinidine A and 40 mol % of 5-
nitrosalycylic acid (5-NSA) in dry toluene at 40 °C for 120 h.
The results for compounds 3ab, 3ba, and 3bb are displayed in
Table 1 and compared with those for product 3aa.
The reaction between inden-1-one 1a and N-Boc-8-amino-β-
naphthol 2b gave compound 3ab as a 90:10 mixture of
conformational diastereoisomers ap-3ab and sp-3ab with a 63%
ee. The rotational barrier was determined to be 83.7 kJ/mol by
means of 1D-EXSY experiment in C2D2Cl4 at 50 °C.7 We then
studied the reaction of 4-bromoindenone 1b with β-naphthol
2a at 20 °C. The desired product 3ba was isolated in 62% yield
and 78% ee. Also, in this case, an 86:14 mixture of ap-3ba and
1
sp-3ba was observed at H NMR in DMSO-d6. The rotational
barrier was found to be 92.1 kJ/mol by 1D-EXSY experiment in
DMSO-d6 at 95 °C. The synergic effect of both substituents
was then tested. The reaction of 1b and 2b furnished ap-3bb as
a single conformational diastereoisomer in 40% yield and 60%
ee. The minor conformer sp-3bb was not observed in the crude
reaction mixture, and this prevented determination the value of
ΔG⧧epi.
Having established that the reaction could be realized with
highly encumbered substrates, we then optimized the
conditions. It was found that catalyst A (20 mol %) in
combination with TFA (40 mol %) in chlorobenzene (0.2 M),
furnished the best yield, enantioselectivity and diastereoselec-
The experimental trends are consistent with our hypothesis
that large substituents and the concomitant presence of a
stereogenic center, cooperate to control the formation of the
thermodynamic ap-conformational diastereoisomer and to
increase the ΔG⧧epi measured for the ap- to sp- interconversion.
However, in the case of compounds with two substituents it is
only possible to observe the thermodynamic effect on the
conformer populations and not the kinetic effect on the
rotational barrier because the minor conformer has never been
B
DOI: 10.1021/acs.orglett.7b03415
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Letter
a
rapidly aromatizes to the most stable C(sp3)−C(sp2)
Table 2. Scope of the F−C-Type Alkylation
conformational diastereoisomer (Scheme 4).
Scheme 4. Proposed Catalytic Cycle
As a final part of our work, we explored possible
derivatizations of our products. We realized a large-scale
catalytic reaction between 1b and 2e followed by reduction/
deprotection of ap-4be with NaBH4 in methanol at 60 °C. The
desired indanol ap-5be was obtained in 84% overall yield and
>99% de and 94.5% ee (Scheme 5).
Scheme 5. Derivatization of Indanones
a
Reactions performed with 1b−e (0.2 mmol) and 2b−k (0.22 mmol)
In conclusion, by developing the reported enantioselective
F−C-type alkylation between substituted indenones and
naphthols we were able to exert thermodynamic control over
the C(sp3)−C(sp2) stereogenic axis conformation and realize
the selective synthesis of the ap-conformational diaster-
eoisomer. The trend observed during the optimization would
suggest the possible existence of this kind of compounds as
novel C(sp3)−C(sp2) atropisomers. Further experiments are
ongoing to study the feasibility of an atroposelective process.
b
c
in 1 mL of chlorobenzene. Isolated yield. Determined by HPLC
analysis. Determined by H NMR.
d
1
detected. DFT calculation9 suggested that sp-3bb is 16.7 kJ/
mol higher in energy than ap-3bb and estimate an energy
barrier for the ap-3bb to sp-3bb interconversion of 105.5 kJ/
mol.10 The huge 16.7 kJ/mol difference between the two
ground states can easily explain why the sp-conformation (if
produced by the reaction) cannot be detected after the
reaction. The energy barrier for interconversion into the major
conformer is 88.8 kJ/mol, a value that implies complete
interconversion during the course of the 56 h of the reaction.
This aspect does not exclude that our diastereomeric
conformers are atropisomers.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03415.
From the X-ray structures of ap-4bf, we can advance a
transition state where the addition of 2f takes place at the Si
face of 1b. A plausible model which minimizes the steric
interactions and favors the approach at the Si face over the Re
face of the iminium ion, can be rationalized using hydrogen
bonding interactions between the catalytic salt and the hydroxy
group of naphthol.11 After the alkylation, only one of the two
C(sp3)−C(sp3) intermediates in equilibrium with each other
General experimental procedures and characterization
data for new compounds (PDF)
Accession Codes
CCDC 1534642, 1534643, and 1534644 contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
C
DOI: 10.1021/acs.orglett.7b03415
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(7) Determined on the corresponding acetylated 4ab via 1D-EXSY
experiment. The ap/sp ratio after acetylation is 96:4.
(8) See the Supporting Informations for details.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
(9) Gaussian 09, Revision D.01. Frisch, M. J.; Trucks, G. W.; Schlegel,
H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.;
Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato,
M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.;
Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;
Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai,
H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.;
Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.;
Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J.
C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene,
M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.;
Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.;
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: giorgio.bencivenni2@unibo.it.
ORCID
Nicola Di Iorio: 0000-0002-4431-4007
Giacomo Filippini: 0000-0002-9694-3163
Andrea Mazzanti: 0000-0003-1819-8863
Paolo Righi: 0000-0003-1419-2560
Giorgio Bencivenni: 0000-0002-0855-1232
Notes
̈
Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.;
The authors declare no competing financial interest.
Cioslowski, J.; Fox, D. J. Gaussian, Inc.: Wallingford, CT, 2009.
(10) In the case of compound 4be, DFT calculations estimated that
the ap-conformer is more stable than the sp- by 16.3 kJ/mol. In the
case of 3be, the deacetylated form of 4be, the same DFT calculation
estimated a rotational energy barrier for the ap- to sp interconversion
of 107.5 kJ/mol. See the Supporting Information for details.
(11) Moran, A.; Hamilton, A.; Bo, C.; Melchiorre, P. J. Am. Chem.
Soc. 2013, 135, 9091.
ACKNOWLEDGMENTS
■
We are grateful to the University of Bologna for the financial
support. We express our gratitude to Dr. Silvia Ranieri from the
University of Bologna for her contribution for DFT
calculations.
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