Utilization of BozPhos as an Effective Ligand in Enantioselective C-H Functionalization of Cyclopropanes: Synthesis of Dihydroisoquinolones and Dihydroquinolones

Article abstract of DOI:10.1021/acs.orglett.9b00627

The bisphosphine monoxide (R,R)-BozPhos enables enantioselective C-H functionalization of cyclopropanes in a palladium-catalyzed cyclization. The synthesis of a broad spectrum of dihydroisoquinolones and dihydroquinolones in good yields and high enantiomeric excess was achieved through the use of this hemilabile ligand. Furthermore, the isolation of an intermediary palladium(II)-BozPhos complex after oxidative addition was successful and a second complex provided further insight into bond length and angles through a crystal structure.

Full text of DOI:10.1021/acs.orglett.9b00627

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Utilization of BozPhos as an Effective Ligand in Enantioselective
C−H Functionalization of Cyclopropanes: Synthesis of
Dihydroisoquinolones and Dihydroquinolones
́
Camilla Mayer, Carolyn L. Ladd, and Andre B. Charette*
́
́
FRQNT Centre in Green Chemistry and Catalysis, Department of Chemistry, Universite de Montreal, P.O. Box 6128, Station
́
Downtown, Montreal, Quebec, Canada, H3C 3J7
S
* Supporting Information
ABSTRACT: The bisphosphine monoxide (R,R)-BozPhos
enables enantioselective C−H functionalization of cyclo-
propanes in a palladium-catalyzed cyclization. The synthesis
of a broad spectrum of dihydroisoquinolones and dihydro-
quinolones in good yields and high enantiomeric excess was
achieved through the use of this hemilabile ligand.
Furthermore, the isolation of an intermediary palladium(II)-
BozPhos complex after oxidative addition was successful and a second complex provided further insight into bond length and
angles through a crystal structure.
Scheme 1. Use of BPMOs as Ligands in Palladium- and
Copper-Catalyzed Reactions
igands have tremendous influence on the regio-, chemo-,
and, of course, stereoselectivity in metal-catalyzed
L
reactions. Chiral bisphosphines, in particular, stand out in
the group of ubiquitous phosphine ligands and found their
application in a variety of asymmetric reactions.1 Over the
years, diverse bisphosphines, capable of controlling selectivity
and reactivity through their different bite angles and their
varying steric and electronic influence, were developed.2 In
1996, the group of Shimizu reported an enantioselective
elimination, which gave either the (R)- or the (S)-enantiomer
depending on the ratio of Pd(OAc)2 and (S)-BINAP.3 This
initial contradictory observation was due to the formation of
the corresponding bisphosphine monoxide (BPMO) (S)-
BINAP(O). The in situ oxidation of bisphosphine ligands is
more easily noticed in the case of reversed selectivity4
compared to enhanced or superior performance.5 There is a
high probability that, in some cases, the formation of BPMO as
the active ligand, although occurring, was not detected.6 In our
group, for example, we observed that the high enantioselec-
tivity obtained in the addition of diorganozinc reagents on
imines was due to (R,R)-BozPhos7 instead of the initially used
(R,R)-Me-DuPhos8 (Scheme 1).
BPMOs are hemilabile ligands containing both a soft (P)
and a hard (PO) Lewis base center. Therefore, they form
weak chelating complexes with transition metals resulting in
lower activation energy for transformations such as isomer-
ization, ligand exchange, and oxidative addition.9 Although
they are rarely used compared to other phosphine ligands,
BPMOs have been employed as excellent ligands in polymer-
ization reactions,10 conjugative addition and reduction,11
asymmetric Heck reaction,12 [4 + 2 + 2] cycloaddition,13
and carboiodination.14
XantPhos to the corresponding monoxide occurred in situ
through reduction of palladium(II) to palladium(0) (Scheme
1).16 The unique bond properties17 of cyclopropanes
combined with their importance in the development of new
drug candidates18 make them highly interesting targets, and a
few procedures for the enantioselective C−H activation were
developed so far.19,20 In preliminary results, our group showed
the successful application of BozPhos in the intramolecular
Blackmond and Eastgate were the first to report a C−H
Received: February 19, 2019
functionalization with a BPMO.15 In this case, the oxidation of
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00627
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
alkenylation of cyclopropanes (Scheme 1).21 However, this
first and only report to date of enantioselective C−H
functionalization employing directly a BPMO was only a
preliminary result with either a moderate yield or enantiose-
lectivity depending on the palladium source. Inspired by this
result, we wanted to further investigate their potential and
aimed for the synthesis of dihydroisoquinolones. A procedure
leading to racemic material was developed by our group,22 and
Cramer reported in 2015 an enantioselective version of this
reaction. They successfully used a Taddol-based phosphor-
amidite as their ligand.23
enantioselective C−H functionalization. First, we varied the
substituent on the cyclopropane ring (R1) (Scheme 2). The
Scheme 2. Scope with Variation on the Nitrogen and the
a
Cyclopropyl Substituent
We decided to use benzamide 1a as a model substrate for
the optimization. We were delighted to obtain 2a in good yield
and enantiomeric excess (ee) with Pd(OAc)2 and BozPhos
(entry 1, Table 1). However, palladium(II) has the ability to
Table 1. Optimization of the Enantioselective C−H
Functionalization
entry
[Pd]
acid
base
yield
ee
1
2
3
4
5
6
7
8
9
10
11
12
13
Pd(OAc)2
Pd(PPh3)4
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd G4 dimer
Pd(OAc)2
Pd G4 dimer
Pd G4 dimer
Pd G4 dimer
AdOH
AdOH
AdOH
AdOH
AdOH
AdOH
AdOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
Cs2CO3
Cs2CO3
Cs2CO3
KOtBu
K3PO4
K2CO3
Rb2CO3
Rb2CO3
Rb2CO3
Rb2CO3
Rb2CO3
Rb2CO3
Rb2CO3
84%
99%
95%
15%
58%
63%
97%
95%
95%
62%
91%
90%
95%
81%
25%
77%
87%
91%
77%
85%
90%
92%
61%
80%
93%
93%
a
The reactions were performed on a 150 μmol scale unless otherwise
b
c
d
stated. At 110 °C. 1.0 mmol scale in xylene (0.6 M) at 115 °C. 115
μmol scale. 136 μmol scale. At 100 and 130 °C.
e
f
nitrile group (2b) and phenyl group (2c) were tolerated and
gave satisfying results. Benzyl (2d) and alkyl substituted
substrates (2e, 2f) also gave good results. The comparison
between the methyl (2e) and isopropyl group (2f) showed that
a more steric demanding substituent gave a higher
enantioselectivity. Similar influence was observed with
substituents on the nitrogen (R2). The benzyl substituent
(2g) again gave a lower ee compared to the methyl group
whereas the isopropyl substituent (2h) improved it. Substrates
with tert-butyloxycarbonyl and benzoyl groups on the nitrogen
(R2) did not undergo the C−H activation under these
conditions. Some of the substituents on the cyclopropane
ring (1d−f) as well as on the nitrogen (1g−h) could also
undergo C−H activation. However, the reactions proceeded as
expected29 chemoselectively and no other product besides 2
was observed in any of those cases. The utilization of a
spirocyclopropane (1i) failed, and unfortunately the formation
of a seven-membered cycle (2j) was also unsuccessful.
a
b
ac
,
ad
,
ae
,
a
2.5 mol % of the catalyst was used, and the reaction was done in
xylene for 17 h. (R,R)-Me-DuPhos (5 mol %) was used instead of
BozPhos, and water (40 mol %) was added. 5 mol % BozPhos was
used. 30 mol % BozPhos was used. At 100 °C.
b
c
d
e
oxidize the BPMO to the less reactive dioxide.5c,9 To avoid this
undesired oxidation, we tested different palladium(0) sources.
The use of Pd(PPh3)4 resulted in poor enantioselectivity
probably due to the competition of triphenylphosphine as the
ligand (entry 2). Pd(dba)2 turned out to be the better
precatalyst for this reaction (entry 3).
The following base screening revealed rubidium carbonate
as the most suitable base (entries 4−7). After the carboxylic
acid was changed to pivalic acid, the cyclization was achieved
with a 95% yield and 90% ee (entry 8).24 Since the
displacement of dba can be quite challenging25 and can,
therefore, influence the reactivity and selectivity, we used
Buchwald’s fourth generation dimer26 and achieved slightly
improved results (entry 9).27 Unfortunately, our attempts to
use an in situ oxidation28 of Me-DuPhos gave a significantly
lower ee (entry 10). This decreased enantioselectivity can
partly be explained through the necessary 1/1 ratio of ligand to
palladium (entry 11). With the optimized conditions in hand
(entry 13), we investigated the scope and the limitations of this
Next, we evaluated the influence of the aryl substituents (R3)
(Scheme 3). We first examined the influence of fluoro
substituents on different positions (2k−n). While the
cyclization worked well with substitutions on the 4- and/or
5-position, the 6-position was more problematic. The ortho
substituted substrate (1m) was probably less reactive due to
higher steric hindrance and gave only a moderate yield. We
were pleased to see that chloro substituents (2o, 2p) were well
tolerated at those temperatures. When the 2-bromo-6-chloro
functionalized starting material (1p) was used, no bromo-
dihydroisoquinolone could be detected, proving the selectivity
of this reaction. Electron-withdrawing groups have a positive
B
DOI: 10.1021/acs.orglett.9b00627
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Letter
Scheme 3. Different Dihydroisoquinolones with Variation
on the Aryl Group and Dihydroquinolones
Scheme 4. Reaction of the Aryl Chloride
a
After exploring the substrate scope of this reaction, we
wanted to obtain a better understanding of the interaction of
BozPhos with the palladium and our substrate. We succeeded
in isolating the BozPos-palladium(II) complex 4 after oxidative
addition with substrate 1c (Scheme 5).32 The isolated complex
Scheme 5. Syntheses of BozPhos-Palladium Complexes
was air stable, could be purified by standard flash
chromatography over silica gel, and was even stable at
110 °C for several hours without significant decomposition.
Unfortunately, any attempts to obtain high quality crystals for
X-ray crystallography failed. Therefore, we synthesized differ-
ent palladium complexes and were delighted to obtain a crystal
structure of complex 5, which had similarities to a precatalyst
used for C−N coupling.33 Although phosphines bind more
strongly than phosphine oxides to palladium(II), the P(III)−
Pd bond is longer (2.24 Å) than the O−Pd bond (2.18 Å),
which is consistent with reported complexes.15,33,34 The bite
angle (P(III)−Pd−O) of complex 5 measures 80.5°.
Next, we converted complex 4 directly with PivOH and
Rb2CO3 to dihydroisoquinolone 2c. This transformation gave
us surprisingly low enantioselectivity (80% ee) (Scheme 6).
Similar results were observed for the synthesis of ester 2a by
using a 1/1 ratio of BozPhos and palladium instead of 2/1
(Table 1, entry 11). Addition of 5 mol % of BozPhos to the
reaction resulted in previously observed enantioselectivity at
110 °C. NMR experiments of complex 4 in the presence of
BozPhos did not reveal any new species or changes in the
existing complex. BozPhos most likely acts as a monodentate
ligand in the enantioselective concerted metalation−deproto-
nation transition state, and additional BozPhos could therefore
minimize dissociation.35 However, we could not observe a
significant improvement on the enantioselectivity by using a 1/
6 ratio of Pd/ligand (Table 1, entry 12) compared to a 1/2
ratio. At this point, we cannot exclude the possibility that the
second molecule of BozPhos is differently involved in the
mechanism, but further investigations would be necessary.
Last, the isolated complex 4 could be directly used as a catalyst
in the enantioselective cyclization of amide 1c.
a
b
c
The reactions were performed on a 150 μmol scale. At 110 °C. At
d
120 °C. At 130 °C.
influence on the enantioselectivity since the nitro substituted
compound had the highest ee in our scope (2q). The yield of
the pyridine substrate was sufficient, but the enantioselectivity
was unfortunately quite low (19% ee) probably due to
additional binding of the nitrogen to the palladium complex
(2r). The electron-donating methoxy substituted substrate
(2s) worked quite well with slightly lower enantioselectivity
compared to the others. Surprisingly, the dimethoxy substrate
(2t) gave a high ee. Except for the pyridyl derivate, all
synthesized dihydroisoquinolones achieved good results and
the enantioselectivity of the known compounds was higher
compared to the protocol using the Taddol-derived phosphor-
amidite ligand.23 Finally, we also tried to synthesize
dihydroquinolones and we were pleased to see that both
tested substrates worked with satisfying results (2u, 2v).
Ligands have a strong influence on the activation energy of
oxidative additions. While the oxidative addition of aryl
bromides and iodides occurs with palladium relatively easily,
the aryl chlorides show overall lower reactivities.30 However,
BozPhos possesses two properties that should enable the
reaction with chlorides: it is an electron-rich phosphine and it
can act through its hemilabile nature as a monodentate or
bidentate ligand, which facilitate the formation of a possible
monoligated palladium(0) species.31 Under our conditions, we
succeeded in synthesizing dihydroisoquinolone 2a from the
aryl chloride 3 (Scheme 4). Despite the lower enantioselec-
tivity due to the higher temperature, the use of aryl chlorides
can be advantageous in some cases.
C
DOI: 10.1021/acs.orglett.9b00627
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Organic Letters
Letter
C.L.L. thanks the Fonds de Recherche de Nature et
Scheme 6. Further Transformations with Palladium
Complex 3
́
Technologies Quebec for doctoral and postdoctoral fellow-
ships.
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ASSOCIATED CONTENT
* Supporting Information
■
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̈
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glett.9b00627.
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(b) Woste, T. H.; Oestreich, M. Hemilabile BINAP(O) as a Chiral
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Experimental procedures, characterization data, NMR
spectra, and X-ray analysis (PDF)
Accession Codes
CCDC 1898117 contains 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.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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activation using Me-DuPhos and Pd(OAc)2: Anas, S.; Cordi, A.;
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believe that the in situ formed BozPhos could be the active ligand in
this reaction as well. Therefore, we investigated this system and found
that BozPhos and Pd(dba)2 give high ee. See SI for further
information.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: andre.charette@umontreal.ca.
ORCID
̂
́
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Andre B. Charette: 0000-0001-5622-5063
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported through funding from the Natural
Science and Engineering Research Council of Canada
(NSERC) Discovery Grants RGPIN-06438, Leaders Oppor-
tunity Funds 227346, the Canada Research Chair Program
CRC-227346, the FRQNT Centre in Green Chemistry and
́
́
Catalysis (CGCC) RS-171310, and Universite de Montreal.
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