Mizoroki–Heck Cyclizations of Amide Derivatives for the Introduction of Quaternary Centers

Article abstract of DOI:10.1002/anie.201703174

We report non-decarbonylative Mizoroki–Heck reactions of amide derivatives. The transformation relies on the use of nickel catalysis and proceeds using sterically hindered tri- and tetrasubstituted olefins to give products containing quaternary centers. The resulting polycyclic or spirocyclic products can be obtained in good yields. Moreover, a diastereoselective variant of this method gives access to an adduct bearing vicinal, highly substituted sp³ stereocenters. These results demonstrate that amide derivatives can be used as building blocks for the assembly of complex scaffolds.

Full text of DOI:10.1002/anie.201703174

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201703174
German Edition: DOI: 10.1002/ange.201703174
Homogeneous Catalysis
Hot Paper
Mizoroki–Heck Cyclizations of Amide Derivatives for the Introduction
of Quaternary Centers
Jose M. Medina+, Jesus Moreno+, Sophie Racine, Shuaijing Du, and Neil K. Garg*
Abstract: We report non-decarbonylative Mizoroki–Heck
reactions of amide derivatives. The transformation relies on
the use of nickel catalysis and proceeds using sterically
hindered tri- and tetrasubstituted olefins to give products
containing quaternary centers. The resulting polycyclic or
spirocyclic products can be obtained in good yields. Moreover,
a diastereoselective variant of this method gives access to an
adduct bearing vicinal, highly substituted sp3 stereocenters.
These results demonstrate that amide derivatives can be used as
building blocks for the assembly of complex scaffolds.
T
he introduction of quaternary carbon centers remains
a popular topic in modern chemical synthesis.[1] Such motifs
are often difficult to access owing to the steric challenge
associated with constructing a fully substituted carbon center.
One attractive means to install quaternary centers is the
intramolecular Mizoroki–Heck reaction.[2] Most notably, the
Pd-catalyzed Mizoroki–Heck cyclization of aryl halides and
triflates has been the subject of intense investigation for
decades and has been utilized to assemble many sterically
demanding scaffolds. On the other hand, the corresponding
Mizoroki–Heck cyclization of acyl electrophiles to furnish
ketone products bearing quaternary carbon centers has not
been reported.
Figure 1. Nickel-catalyzed Mizoroki–Heck reaction of amide derivatives
to create quaternary centers. Boc=tert-butyloxycarbonyl, Bn=benzyl.
Mizoroki–Heck cyclization of benzoic anhydrides, albeit
without the formation of a quaternary stereocenter,[9,10] and
from Pd-catalyzed carbonylative Mizoroki–Heck reactions of
aryl halides and triflates.[11] Herein, we describe the develop-
ment and scope of a Ni-catalyzed Mizoroki–Heck cyclization
of amide derivatives.[12] The transformation provides a new
means to build complex scaffolds by using non-precious-metal
catalysis.[13]
After some initial experimentation, we arrived at 5 as
a suitable test substrate (Table 1).[14] This substrate contains
the N-Bn,Boc imide motif,[15] which we have previously found
to be reactive using Ni/SIPr (7) combinations,[4,5] in addition
to a sterically encumbered tetrasubstituted olefin. The
Mizoroki–Heck cyclization of 5 was attempted under a variety
of reaction conditions,[16] with a selection of key results using
Ni(cod)2, NHC ligands, and toluene as solvent at 1008C
depicted. Unfortunately, attempts to conduct the desired
cyclization using SIPr·HCl (7) in the presence of NaOtBu
were unsuccessful (entry 1). However, upon switching to
Considering the aforementioned deficiency concerning
the Mizoroki–Heck cyclization of acyl electrophiles, we
pursued the transformation shown in Figure 1. In the
presence of an appropriate nickel catalyst, imides 1, derived
from the corresponding secondary amide through Boc-
activation, should be converted into cyclized products 2,
which bear the desired quaternary centers. Mechanistically,
the conversion would proceed through a sequence akin to
classical Mizoroki–Heck chemistry, involving oxidative addi-
tion (1!3), olefin coordination and insertion (3!4), and b-
hydride elimination[3] (4!2). It should be noted that amide
derivatives have recently been employed in Pd- and Ni-
catalyzed couplings for carbon–heteroatom[4] and carbon–
carbon[5–7] bond formation, although never for the synthesis of
quaternary centers.[8] Moreover, precedent for the desired
olefin insertion is available from Stambuliꢀs Pd-catalyzed
NHC precursor 8, the Mizoroki–Heck product
obtained, albeit in modest yield (entry 2). Further improve-
ments were seen when benzimidazolium salt was
6 was
9
employed,[17] which gave rise to the desired product 6 in
76% yield (entry 3). We also probed the Ni-to-ligand ratio
and found that employing a 1:1 ratio of Ni(cod)2 to 9 (rather
than a 1:2 ratio) led to diminished yields (entry 4). Efforts to
optimize the Ni loading were also undertaken. Although
using 10 mol% Ni(cod)2 gave the desired product (entry 5),
the use of 15 mol% Ni(cod)2 gave excellent yields (entry 6)
and was found to be more generally effective across a range of
substrates studied subsequently. During the course of our
[*] J. M. Medina,[+] J. Moreno,[+] Dr. S. Racine, S. Du, Prof. Dr. N. K. Garg
Department of Chemistry and Biochemistry
University of California, Los Angeles
Los Angeles, CA 90095 (USA)
E-mail: neilgarg@chem.ucla.edu
Homepage: http://garg.chem.ucla.edu
[+] These authors contributed equally to this work.
Supporting information for this article can be found under:
https://doi.org/10.1002/anie.201703174.
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Table 1: Evaluation of ligand effects and reaction conditions for the
conversion of 5 into Mizoroki–Heck cyclization product 6, which bears
a quaternary center.[a]
Table 2: Mizoroki–Heck cyclization of a variety of tri- and tetrasubsti-
tuted olefin substrates.
Entry
1
Alkene
Product
Yield [%][a]
71[b]
2
92[b]
Entry
Ni(cod)2
Loading
[mol%]
Ligand,
Loading
[mol%]
Additive
T [8C]
Yield [%][b]
3
4
5
6
75[b]
51
1
2
3
4
5
6
7
20
20
20
20
10
15
15
7, 40
8, 40
9, 40
9, 20
9, 20
9, 30
9, 30
none
none
none
none
none
100
100
100
100
100
100
60
0
24
76
67
51
91
95
none
t-amyl alcohol[c]
96
[a] Conditions unless otherwise stated: 5 (1.0 equiv, 0.1 mmol), Ni(cod)2
(mol% as shown), 7–9 (mol% as shown), toluene (0.5m), NaOtBu
(1.1ꢀ ligand loading) heated at the specified temperature for 24 h in
a sealed vial. [b] Yields reflect an average of two experiments and were
determined by 1H NMR analysis using hexamethylbenzene as an internal
standard. [c] 3.0 equiv of t-amyl alcohol was used. cod=bis(1,5-cyclo-
octadiene).
80
7
8
91
93
studies, we also evaluated a series of additives used previously
in Ni-catalyzed couplings.[18] These efforts demonstrated that
the reaction temperature could be lowered to 608C, provided
that t-amyl alcohol was employed as the additive, to deliver
product 6 in 95% yield (entry 7).[19] It should be noted that:
1) Ni-catalyzed Mizoroki–Heck reactions to form quaternary
centers are rare,[20] 2) there are no prior examples reported of
Ni-catalyzed Mizoroki–Heck reactions involving tetrasubsti-
tuted olefins,[21] and 3) decarbonylation products were not
observed during reaction development.
Having identified conditions to achieve the nickel-cata-
lyzed cyclization, we evaluated the scope with respect to the
tethered alkene (Table 2).[22,23] It was found that a trisubsti-
tuted olefin[24] analogue of our parent substrate could be
employed to furnish terminal olefin product 10 in 71% yield
(entry 1). We also examined substrates in which the trisub-
stituted olefin was embedded in a ring. Using both 5- and 6-
membered ring substrates, the desired Mizoroki–Heck cycli-
zation proceeded smoothly to give the corresponding spiro-
cyclic products 11 and 12, respectively, as mixtures of olefin
isomers (entries 2 and 3).[25] Returning to the more challeng-
ing tetrasubstituted olefins, a series of substrates bearing
exocyclic olefins were prepared and evaluated. Utilization of
a substrate containing a 5-membered ring led to product 13 in
51% yield (entry 4), and the use of substrates containing 6-
and 7-membered rings furnished products 14 and 15, respec-
tively, in good yields (entries 5 and 6). Finally, two hetero-
[a] Yields shown reflect the average of two isolation experiments.
[b] Reaction performed at 1008C in the absence of t-amyl alcohol.
cyclic substrates were examined. We were delighted to find
that our method proved tolerant of a tetrahydropyran and
a protected piperidine, giving rise to tricycles 16 and 17,
respectively, in excellent yields (entries 7 and 8).
As shown in Figure 2, the method is also tolerant of
substituents on the arene. For example, the use of substrates
containing a fluoride or trifluoromethyl group, both of which
are critical in medicinal chemistry,[26] gave rise to products 18
and 19, respectively. A methoxy group was also well tolerated,
as shown by the formation of 20 and 21. As demonstrated by
the synthesis of 22 and 23, substrates bearing a methyl group
could also be utilized. In the latter case, it is notable that the
presence of a methyl group ortho to the tethered alkene did
not hinder reactivity.
As a further test, we asked whether this reaction could be
performed in a diastereoselective manner (Figure 3). Trisub-
stituted olefin 24,[27] which bears an allylic methyl group, was
treated under our optimal reaction conditions. This reaction
delivered ketone 25 in 80% yield with a 92:8 ratio of
diastereomers. Notably, 25 contains vicinal sp3 stereocenters,
2
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In summary, we have developed a Mizoroki–Heck cycli-
zation of amide derivatives to access ketones containing
quaternary centers. The transformation is tolerant of varia-
tion on both the alkene and aryl moieties, and most notably,
proceeds when using sterically hindered tetrasubstituted
olefins. As a result, polycyclic, spirocyclic, and heteroatom-
containing products can be synthesized using this method.
Moreover, we have demonstrated that a diastereoselective
Mizoroki–Heck cyclization proceeds for the controlled for-
mation of an adduct bearing vicinal, highly substituted sp3
stereocenters. In addition to providing a rare Ni-catalyzed
Mizoroki–Heck cyclization method for accessing quaternary
centers, as well as the first Mizoroki–Heck cyclization of
amide derivatives, our results demonstrate that amides,
despite once being viewed as unreactive, can be used as
building blocks for the preparation of complex scaffolds.
Figure 2. Tolerance of the reaction to substituents on the arene motif.
Acknowledgements
Yields shown reflect the average of two isolation experiments. [a] Yield
1
determined by H NMR analysis using hexamethylbenzene as an
The authors thank the NIH-NIGMS (R01-GM117016), the
Guggenheim Foundation, and the University of California,
Los Angeles, for financial support. We are grateful to the
NIH-NIGMS (F31-GM113642 to J.M.), the UCLA Graduate
Division (Dissertation Year Fellowship and Cota Robles
Fellowship (J.M.M.), the Foote Family (J.M.), the Swiss
National Science Foundation for an Early Mobility Postdoc-
toral Fellowship (S.R.), and the UCLA CSST Program (S.D.).
Professor Daniel Weix (University of Rochester) is thanked
for providing ligands and helpful discussions. These studies
were supported by shared instrumentation grants from the
NSF (CHE-1048804) and the NIH NCRR (S10RR025631).
external standard. [b] Reaction performed at 1008C in the absence of t-
amyl alcohol.
both of which are highly substituted. Prior transition-metal-
catalyzed methods for the synthesis of 2-vinylindanones[23]
have not been demonstrated for the construction of such
complexity. The diastereoselectivity seen in the conversion of
24 into 25 can be rationalized by considering the two
competing olefin insertion transition states, TS1 and TS2. In
both cases, the olefin insertion event is thought to occur via
a standard 4-centered transition state, which prompts allylic
strain arguments.[28] In TS1, A(1,3) strain between the two
highlighted hydrogens is minimal and the methyl group rests
in a pseudo-equatorial disposition. As such, TS1 is favorable
and leads to the major diastereomer of 25 shown, with the
methyl groups residing in a cis fashion. On the other hand, the
minor diastereomer of 25 (not depicted) is thought to arise
from TS2, which displays a less favorable A(1,3) interaction
between the highlighted hydrogen and the methyl substituent.
Conflict of interest
The authors declare no conflict of interest.
Keywords: amides · homogeneous catalysis · Mizoroki–
Heck reactions · nickel · quaternary centers
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[24] This substrate was employed as a 7:1 mixture of E/Z olefins.
[25] See the Supporting Information for details.
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8315 – 8359.
methyl-1-butene and allylic strain arguments, TS2 is estimated to
be roughly 0.7 kcalmolꢀ1 higher in energy than TS1. A review:
R. W. Hoffmann, Chem. Rev. 1989, 89, 1841 – 1860.
Manuscript received: March 27, 2017
[27] This substrate was employed as a 4:1 mixture of E/Z olefins.
Final Article published: && &&, &&&&
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
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Angewandte
Communications
Chemie
Communications
Homogeneous Catalysis
J. M. Medina, J. Moreno, S. Racine, S. Du,
N. K. Garg*
&&&& — &&&&
Mizoroki–Heck Cyclizations of Amide
Derivatives for the Introduction of
Quaternary Centers
Adding complexity: A non-decarbonyla-
tive Mizoroki–Heck reaction of Boc-acti-
vated amide derivatives is reported. The
transformation relies on the use of nickel
catalysis and proceeds using sterically
hindered tri- and tetrasubstituted olefins
to give products containing quaternary
centers. The results demonstrate that
amide derivatives can be used as building
blocks for the assembly of complex scaf-
folds.
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!