Alkyl Group Migration in Ni-Catalyzed Conjunctive Coupling with C(sp3) Electrophiles: Reaction Development and Application to Targets of Interest

Article abstract of DOI:10.1021/acs.orglett.9b04453

A catalytic conjunctive cross-coupling reaction is developed that allows the construction of chiral organoboronic esters from alkylboron ate complexes and alkyl iodide electrophiles. The process occurs most efficiently with a Ni/Pybox-comprised catalyst a

Full text of DOI:10.1021/acs.orglett.9b04453

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Letter
Alkyl Group Migration in Ni-Catalyzed Conjunctive Coupling with
C(sp3) Electrophiles: Reaction Development and Application to
Targets of Interest
Seung Moh Koo, Alex J. Vendola, Sarah Noemi Momm, and James P. Morken*
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ABSTRACT: A catalytic conjunctive cross-coupling reaction is developed that allows the construction of chiral organoboronic
esters from alkylboron ate complexes and alkyl iodide electrophiles. The process occurs most efficiently with a Ni/Pybox-comprised
catalyst and with an acenapthoquinone-derived boron ligand. Because of the broad functional group tolerance of this reaction, it can
be a versatile tool for organic synthesis. Applications to the construction of (R)-coniine and (−)-indolizidine 209D are described.
Scheme 1. Conjunctive Cross-Coupling with Alkenylboron
Ate Complexes
rganoboronic acid derivatives are useful reagents in
organic synthesis,1 are important structures in medicinal
O
chemistry2 and chemical biology,3 and have found applications
in sensor technology and material science.4 One can prepare
organoboron compounds with a variety of a different methods;
however, there are gaps in synthetic methodology that hinder
access to certain structural classes. This is especially the case if
one wishes to use catalytic reactions to construct compounds
with boron-containing stereogenic centers.5 For instance, while
a number of reactions can produce secondary boronic esters in
a catalytic enantioselective fashion, most of these trans-
formations, as a consequence of their underpinning reaction
mechanism, will lead to specialized products that contain sp2
carbons, directing groups, carbonyls, or other particular
functional groups at defined locations. In so far as we are
aware, the asymmetric catalytic Negishi coupling of α-
chloroboronic esters (Scheme 1, eq 1) developed by Fu is
the only process able to furnish nonracemic secondary
organoboronic esters containing simple alkyl substituents.6 In
this paper, we present an alternate catalytic enantioselective
route to nonfunctionalized organoboronic esters and show that
a number of functional groups can be included at sites
necessary to enable subsequent chemical synthesis.
of nickel complexes in conjunction with a pyridylbisoxazoline
(pybox) ligand as the catalyst allowed for the use of C(sp3)
electrophiles and promised to broaden the scope of this
reaction substantially.10 A critical limitation of the Ni/pybox-
The conjunctive cross-coupling between organic electro-
philes and alkenylboron “ate” complexes (Scheme 1, eq 2) is
an efficient process that can furnish enantiomerically enriched
organoboronic esters in a catalytic fashion.7,8 This reaction
occurs by way of a 1,2-metalate shift wherein a substituent
attached to the boron atom migrates to the α-carbon of the
adjacent alkene with concomitant C−M bond formation
occurring at Cβ (see Scheme 1 inset).9 While initial studies
employed palladium catalysts and C(sp2) electrophiles, the use
Received: December 12, 2019
https://dx.doi.org/10.1021/acs.orglett.9b04453
© XXXX American Chemical Society
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Letter
catalyzed process, however, was that aliphatic boron
substituents were found to be recalcitrant migrating groups,
and therefore, the reaction was limited to construction of
benzylic boronic esters. In this study, we examine the Ni/
pybox-catalyzed coupling of C(sp3) electrophiles with alkyl-
(vinyl)boron-derived ate complexes (Scheme 1, eq 3) and
show that the boron ligand can be tuned to facilitate an
effective reaction.
delivered the conjunctive coupling product in about 65% yield
and 99:1 enantiomer ratio when conducted at room temper-
ature (entry 9).
With a workable catalytic system that allows the migration of
aliphatic groups in conjunctive couplings with aliphatic
electrophiles, we surveyed a number of other substrates. As
depicted in Scheme 2, migrating chains that bear functional
Examination of the conjunctive coupling between a
pinacolato alkylboron-derived ate complex and (3-
iodopropyl)benzene demonstrated the lack of reactivity with
this class of boron reagent. Whereas the analogous phenyl-
derived ate complex undergoes coupling in 70% yield (data not
shown), as depicted in Table 1 (entry 1) when the migrating
Scheme 2. Scope of Ni-Catalyzed Conjunctive Coupling
with B(mac)-Derived Ate Complexes
a
Table 1. Optimization of Ni-Catalyzed Conjunctive
Coupling of a C(sp3) Electrophile with an
a
Alkyl(vinyl)boronate Complex.
yield of 3
(%)
entry (OR)2
modifications
er
1
2
3
4
5
6
7
pin
neo
none
none
4
6
n/d
n/d
99:1
n/d
n/d
n/d
99:1
mac none
mac 5% Ni(cod)2
mac 5% NiBr2·glyme
mac 5% [methallyl)NiCl]2[Ni], 12% L1
35
16
11
41
53
mac 5% [methallyl)NiCl]2,
12% L1, 3:1 THF/DMSO
8
9
mac 10% [(TMEDA)Ni(o-tol)Cl],
12% L1, 3:1 THF/DMSO
mac 10% [(TMEDA)Ni(o-tol)Cl],
12% L1, 3:1 THF/DMSO, rt
55
65
99:1
>99:1
a
a
Yield refers to isolated yield of purified product. er refers to the
Yield refers to isolated yield of purified product. er refers to the
enantiomeric ratio and was determined by SFC chromatography on a
chiral stationary phase. Reaction employed the pinacol-derived
boronate. Reaction with the pinacol-derived boronate and at 45 °C.
enantiomeric ratio and was determined by SFC chromatography on a
chiral stationary phase.
b
c
group is an n-butyl chain, the product obtained upon oxidation
of 1 is formed in only 4% yield. Examination of the byproducts
in entry 1 showed that one competing side reaction is the
alkylation of the pinacol ligand with the electrophile. To avoid
this circumstance, we considered other boron ligand frame-
works that might be either less basic or more sterically
encumbered. As depicted in entries 2 and 3, replacement of
pinacol with a neopentylglycolato group resulted in only 6%
product yield, whereas use of acenapthoquinone-derived
“mac”11 ligand led to a substantial improvement in reaction
outcome: after oxidation of the boronic ester intermediate (2),
the alcohol was isolated in 35% yield. Subsequent optimization
led to further improvements: the use of increased catalyst
loading (10% catalyst), the use of THF/DMSO mixture as the
reaction solvent, and the use of [(TMEDA)Ni(o-tol)Cl] as the
source of Ni ion resulted in a process that reproducibly
groups such as an alkene (4), ether (5), ketal (6), and
carbamate (21) are accommodated in this reaction. In contrast
to the Pd-catalyzed process that allows migrations of secondary
and tertiary aliphatic groups,7a,b,f the Ni-catalyzed process
appears to be much more sensitive to steric effects: migration
of an isopropyl group from a B(mac)-derived ate complex
occurred in only 32% yield. Of note, use of the pinacol derived
ate complex could improve the yield of these more hindered
substrates (18−20); however, the overall efficiency of these
reactions still remains modest.
In terms of the electrophile, the experiments in Scheme 2
suggest that the alkyl iodide component could have silyl (9)
and alkyl ethers (10, 11), ketals (13), esters (14), and Boc-
protected amines (15). It was also found that the alkyl iodide
itself could contain a pinacol boronic ester and, in the case of
B
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16, provides a route to a 1,6-diboronate. Lastly, while
secondary iodides proved reactive (11), they gave lower yields
than primary electrophiles (12% yield with cyclopentyl iodide,
data not shown).
Scheme 5. Preparation of (−)-Indolizidine 209D by Ni-
Catalyzed Conjunctive Cross-Coupling
To assess the usefulness of the Ni(pybox)-catalyzed
conjunctive coupling in preparative synthetic chemistry, we
first examined the ability of this process to proceed effectively
on larger scale. As depicted in Scheme 3, when 1.56 g of
Scheme 3. Gram-Scale Conjunctive Coupling
vinylB(mac) was treated with n-BuLi, followed by the catalyst
and (3-iodopropropyl)benzene in THF/DMSO at room
temperature for 22 h, the conjunctive coupling product 2
was isolated in 65% yield and with an enantioselectivity of
99.3:0.7 er. That the selectivity and efficiency for this process
so closely mirror that observed on smaller scale bodes well for
the general use of this reaction in chemical synthesis.
To learn whether the conjunctive coupling might accom-
modate reactive functional groups that would be useful in the
preparation of relevant alkaloid synthesis targets, we examined
preparation of motifs that could participate in boronic ester
amination or reductive amination. In the first scenario, the
synthesis of enantiomerically enriched Boc-protected coniine12
was addressed. To access this structure, an alkyl iodide bearing
an alkoxyamine was employed in the conjunctive coupling. In
this case, product 22 (Scheme 4) was accessed in good yield
coupling with an electrophile bearing appropriately positioned
ketal and benzyl ether functional groups. This reaction
delivered compound 25 in good yield and >99:1 er.
Subsequent amination of the boronic ester (to give 26),
followed by ketal hydrolysis and imine reduction provided
piperidine 27, which was then converted to the target 28 by a
known route14c involving debenzylation and substitution at the
primary carbon.
In conclusion, the use of the “mac diol” ligand allows alkyl
boronic ester-derived ate complexes to participate in highly
selective conjunctive coupling reactions with aliphatic electro-
philes. The reaction can be conducted on preparative scale and
can accommodate a range of useful organic functional groups.
We anticipate that these features will make this process useful
to the synthetic chemist.
Scheme 4. Preparation of (R)-Coniine by Ni-Catalyzed
Conjunctive Cross-Coupling
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04453.
Procedures, characterization and spectral data(PDF)
AUTHOR INFORMATION
Corresponding Author
■
James P. Morken − Boston College, Chestnut Hill,
Massachusetts; orcid.org/0000-0002-9123-9791;
Email: morken@bc.edu
Other Authors
Seung Moh Koo − Boston College, Chestnut Hill,
Massachusetts
Alex J. Vendola − Boston College, Chestnut Hill,
Massachusetts
Sarah Noemi Momm − Boston College, Chestnut Hill,
Massachusetts
and outstanding enantioselectivity. Subsequent removal of the
Boc carbamate, followed by intramolecular amination13 of the
organoboronic ester, and Boc protection (to facilitate
isolation) delivered the product 24 in an efficient fashion.
As an alternate route to alkaloid natural products, we
considered the reductive amination applied to substrates
derived from conjunctive coupling. As shown in Scheme 5,
(−)-indolizidine 209D14 was prepared by conducting the
Complete contact information is available at:
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C
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Letter
Chem. 2006, 71, 7016. (d) Daly, M.; Gill, K.; Sime, M.; Simpson, G.
L.; Sutherland, A. Org. Biomol. Chem. 2011, 9, 6761.
(13) For the intermolecular version of this process, see:
(a) Mlynarski, S. N.; Karns, A. S.; Morken, J. P. J. Am. Chem. Soc.
2012, 134, 16449. (b) Edelstein, E. K.; Grote, A. C.; Palkowitz, M. D.;
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(14) Isolation: (a) Daly, J. W.; Spande, T. F.; Garraffo, H. M. J. Nat.
Prod. 2005, 68, 1556. Recent syntheses: (b) Kim, G.; Shim, J. H.;
Kim, J. H. Bull. Korean Chem. Soc. 2003, 24, 1832. (c) Coia, N.;
Mokhtari, N.; Vasse, J.-L.; Szymoniak, J. Org. Lett. 2011, 13, 6292.
(d) Chiou, W.-H.; Chen, H.-Y. RSC Adv. 2017, 7, 684.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the NIH (R35-GM1217140).
■
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