Allyl-Nickel Catalysis Enables Carbonyl Dehydrogenation and Oxidative Cycloalkenylation of Ketones

Article abstract of DOI:10.1021/jacs.9b02552

We herein disclose the first report of a first-row transition metal-catalyzed α,β-dehydrogenation of carbonyl compounds using allyl-nickel catalysis. This development overcomes several limitations of previously reported allyl-palladium-catalyzed oxidation, and is further leveraged for the development of an oxidative cycloalkenylation reaction that provides access to bicycloalkenones with fused, bridged, and spirocyclic ring systems using unactivated ketone and alkene precursors.

Full text of DOI:10.1021/jacs.9b02552

Subscriber access provided by ECU Libraries
Communication
Allyl-Nickel Catalysis Enables Carbonyl Dehydrogenation
and Oxidative Cycloalkenylation of Ketones
David Huang, Suzanne M. Szewczyk, Pengpeng Zhang, and Timothy R. Newhouse
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b02552 • Publication Date (Web): 12 Mar 2019
Downloaded from http://pubs.acs.org on March 12, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 6
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Allyl-Nickel Catalysis Enables Carbonyl Dehydrogenation and
Oxidative Cycloalkenylation of Ketones
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
David Huang, Suzanne M. Szewczyk, Pengpeng Zhang, and Timothy R. Newhouse*
Department of Chemistry, Yale University, 225 Prospect St., New Haven, Connecticut 06520-8107
Supporting Information Placeholder
ABSTRACT: We herein disclose the first report of a first-row
transition metal-catalyzed ,-dehydrogenation of carbonyl
compounds using allyl-nickel catalysis. This development
overcomes several limitations of previously reported allyl-
palladium-catalyzed oxidation, and is further leveraged for the
development of an oxidative cycloalkenylation reaction that
provides access to bicycloalkenones with fused, bridged, and
spirocyclic ring systems using unactivated ketone and alkene
precursors.
Methodological advancements in the area of transition metal
catalysis have enabled challenging C–C bond formations using
unstabilized enolates. Among these advancements are -
alkenylation reactions1 that employ a cross-coupling strategy
(Figure 1A) to unite a vinyl halide and a metal enolate to provide
synthetically versatile ,-enone products. As an alternative to
cross coupling, seminal work by Saegusa2 and Kende3
demonstrated that unactivated alkenes can be employed for the
cycloalkenylation4 of ketones using palladium, but required the
pre-activation of the carbonyls as enoxysilanes (Figure 1B).
Additionally, stabilized enolates,5 such as 1,3-diketones can also be
employed in cycloalkenylation reactions, including using
palladium catalysis as reported by Widenhoefer.6
As existing strategies for -alkenylation require either activated
ketone or alkene partners,5
a direct alkenylation between
unactivated ketones and alkenes by an oxidative approach would
advantageously allow for the employment of more abundantly
available precursors, and contribute to increased step-efficiency for
cycloalkenylation reactions, which are broadly used in natural
product synthesis for the construction of carbocycles.4b
Given our previous success using allyl oxidants to promote -
hydride elimination in the context of palladium-catalyzed carbonyl
dehydrogenation (10),7,8 we hypothesized that allyl-transition
metal catalysis could also facilitate our desired dehydrogenative
cycloalkenylation. In particular, we were interested in probing the
possibility of using allyl-nickel catalysis to facilitate the desired
cycloalkenylation reaction due to nickel’s increased propensity to
undergo migratory insertion.9
Figure 1. Strategies for -Alkenylation of Ketones
which completes the catalytic cycle via oxidative addition to allyl
electrophile 9. Additional mechanistic support comes from Tsuji’s
observation that allyl-palladium enolates generated by the
decarboxylation of allyl -ketoesters could undergo migratory
insertion and -hydride elimination with electron-deficient alkenes
to give cycloalkenylation adducts.10
The envisioned oxidative cycloalkenylation reaction involves
generation of allyl-nickel enolate 4 by deprotonation of 1 followed
by transmetalation with allyl-nickel species 3. A subsequent
migratory insertion event with a pendant alkene would generate
alkyl-nickel species 5 that then undergoes -hydride elimination to
give the desired cycloalkenylation product (2) and allyl-nickel-
hydride (6). Catalyst turnover by reductive elimination of 6 gives
propene as the stoichiometric byproduct and Ni(0),
Despite the often more challenging -hydride elimination of
first-row transition metals,9 successful development of this
methodology would provide a more sustainable and cost-effective
alternative for allyl-metal-catalyzed -hydride elimination in both
cycloalkenylation and carbonyl ,-dehydrogenation contexts. We
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 6
also aimed to leverage the inherent differences of first- and second-
row transition metals to address some of the current limitations of
allyl-palladium-catalyzed dehydrogenation chemistry. In
particular, for reluctant substrates that give predominantly Tsuji-
Trost allylation byproducts, we expected the use of a less
electrophilic allyl-nickel species to be more successful.
substrate class for this nickel-catalyzed dehydrogenation, including
sterically hindered ,-disubstituted amide 10o. When we tried
1
2
3
4
Table 2. Scope of Carbonyl and Nitrile ,-
Dehydrogenation
5
Unactivated carbonyl compounds can undergo ,-
dehydrogenation by several methods including using metal
catalysis.11 Stahl has reported an exciting process for ketone and
aldehyde dehydrogenation using palladium catalysis that is
beginning to see widespread adoption.12 Dong has also reported a
palladium-catalyzed approach for lactams,13 and more recently a
method employing platinum to dehydrogenate several substrate
classes.14 Methods utilizing first-row metals for dehydrogenation
have either focused on activated systems that lead to products with
extended conjugation, or these intermediates were not isolated but
rather reacted further to form more stable products.15 This report
describes the first practical first-row transition metal-catalyzed
,-dehydrogenation of carbonyl compounds using nickel-
catalysis. The discovery of nickel-catalyzed dehydrogenation was
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a
starting point for the development of an oxidative
cycloalkenylation of ketone enolates for the construction of diverse
bicyclic scaffolds.
Ketone 11a was used as our model substrate (Table 1) as we
previously identified that acyclic ketones were poor substrates for
our reported allyl-palladium catalyzed ketone dehydrogenation
protocol (entry 1).8 Several first-row metal catalysts were
investigated (entries 2-6), and encouragingly we were excited to
find that a similar, albeit low yield of enone 10a could be detected
using NiBr2(dme) (entry 6), demonstrating the feasibility of a
nickel-mediated reaction. Investigation of the base (entries 7–9)
revealed that our previously disclosed hindered lithium anilide
base, LiCyan, proved to be most effective.7b
Table 1. Optimization of ,-Dehydrogenation
a1H-NMR yield was determined using 1,3,5-trimethoxybenzene as
an internal standard.
b
a1.2 equiv Zn(TMP)2 and no ZnBr2 was used. 1,4-dioxane was
c
o
d
used as solvent. Reaction conducted at 23 C. 1.0 equiv diethyl
allyl phosphate was used.
We investigated the scope of the nickel-catalyzed
dehydrogenation with particular interest in other substrates that
were previously unsuccessful with the palladium-catalyzed system
(Table 2). A variety of acyclic ketones, including aliphatic (10a–c)
and electron-rich aryl ketones (10d–e) were efficiently
dehydrogenated under the optimized conditions, and tolerated acid
sensitive acetal and cyclopropane functionality. Primary (10f) and
more hindered secondary nitriles (10g–j) were also excellent
substrates for this nickel-catalyzed dehydrogenation. Notably, -
aryl nitriles (10i–j), which predominantly gave allylation
byproducts when palladium was used, were efficiently
dehydrogenated using the less electrophilic allyl-nickel system.
Similarly, -aryl ester 10k was also accessed in good yield.
Unsaturated ester 10l containing N-Piv functionality was also
obtained in excellent yield. Amides (10m–o) were a viable
our optimized conditions on cyclic ketones, we saw significantly
depreciated yields. Instead we found that commercially available
Zn(TMP)2 was most effective for cyclic ketones, as previously
demonstrated.8 -ketoester 10p could be dehydrogenated in good
yield, despite the possibility of metal chelation by the 1,3-
dicarbonyl suppressing reactivity. Ketone 10q containing a pendant
alkene and mutilin derivative 10r could also be accessed.
Interestingly, we found that Zn(TMP)2 also efficiently
dehydrogenated 5-, 6-, and 7-membered lactones (10s–u) and
lactams (10v–x) despite their decreased acidity. Notably,
unsaturated lactam 10v is a key intermediate needed to access an
important class of IRAK4 inhibitors.16 While LiCyan is still an
effective base for lactones and lactams, it was generally observed
ACS Paragon Plus Environment

Page 3 of 6
Journal of the American Chemical Society
that Zn(TMP)2 outperformed LiCyan for cyclic carbonyl
and bicyclo[3.2.1]octanes (2u), which are important core structures
in a variety of natural products,19 could be accessed despite the
possibility of hydride elimination. Access to
1
2
3
4
compounds (see Supporting Information). The use of Zn(TMP)2
also provides the advantage of a more operationally simple
protocol. Under our reaction conditions, structural features of the
molecule (acyclic or cyclic) seem to dictate the optimal base
necessary for efficient dehydrogenation.
Table 3. Scope of Oxidative Cycloalkenylation
5
6
7
8
Furthermore, the development of a nickel-catalyzed system for
carbonyl dehydrogenation overcomes previous limitations in
scope, such as acyclic ketones (10a–d) and allylation-prone -aryl
substrates (10i–k) and provides an efficient and cost-effective
alternative for carbonyl dehydrogenation, which has only been
demonstrated previously with precious metals.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Using our newly established allyl-nickel-based system, we then
explored the possibility of an oxidative cycloalkenylation of
ketones. It was found that with only a minor modification to the
dehydrogenation conditions using Zn(TMP)2 as base, the desired
cycloalkenylation could be achieved. The addition of ZnBr2 as an
additive was crucial for attaining an efficient reaction and a broad
substrate scope (see Supporting Information for
a broad
investigation of additives), and highlights the remarkable role of
salt additives in transformations involving organozinc species.17
The substrate scope was explored with particular interest in the
various carbocyclic architectures that could be accessed (Table 3).
Acyclic ketones could efficiently cyclize with a pendant homoallyl
group, providing -methyl cyclohexenone products after alkene
isomerization to the more thermodynamically stable ,-enone
products (2a–d). Importantly, ethyl ketones could also be used
despite the possibility of dehydrogenation, providing access to
tetrasubsituted enone 2b. Enone product 2c highlights that this
protocol is selective for cyclization of 6-membered rings rather
than 5-membered rings, which is in contrast to previous reports of
palladium-mediated cycloalkenylations.4 Gratifyingly, sensitive
furan functionality was also well tolerated (2d). Geminally
substituted cyclic structures could be used to access spirocyclic
motifs in good yields (2e–h) and tolerated the acid sensitive N-Boc
(2f) and acetal functionality (2g–h).
Bicyclo[4.3.0]nonanes and bicyclo[4.4.0]decanes could also be
accessed using this methodology as demonstrated products 2i–q.
Access to piperitone derivative 2i highlights that 5-membered ring
formation is also possible, and 2i was prepared on 1-gram scale
without any depreciation in yield. Access to ,-enone product 2j
was previously reported in the literature to be a challenging
transformation by a number of approaches and leads to eudesmane-
type sesquiterpene natural products.18 Gratifyingly, pendant
alkenes bearing electron withdrawing groups were also tolerated in
the substrate scope and could provide ,-unsaturated ester product
2k as
a 2:1 mixture of separable E- and Z-isomers.
Cycloalkenylation with olefins bearing electron-donating
substituents such as alkyl or ether groups were not tolerated. Other
bicyclo[4.3.0]nonanes (2l–n), such as verbenone derivative 2l
bearing an acid-sensitive cyclobutane and Boc-protected indole 2n
were also excellent substrates under the reaction conditions.
Cycloalkenylation initiated by cyclopentanones could also be
achieved (2o–q) and demonstrated the tolerance of benzonitrile
(2p) and TBS-protected alcohol functionality (2q). Indanone 2o
was accessed using modified reaction conditions that employed 20
mol % catalyst loading and no ZnBr2 additive, which was found to
be an excellent alternative for reluctant substrates. Notably, while
6-membered ring formation under previously reported
cycloalkenylation methods with palladium is challenging,2,4 this
allyl-nickel system provides an efficient disconnection for forming
cyclohexanes with unactivated alkenes.
b
a2.0 equiv of Zn(TMP)2 was used. 20 mol % NiBr2(dme) and no
ZnBr2 was used. c40 oC. d1.5 equiv Zn(TMP)2 was used.
bicyclo[3.3.1]nonane 2r demonstrates the possibility of bifurcating
reactivity using reagent control (Table 2, 10q), although this was
not found to be a general phenomenon. Wieland-Miescher ketone
derivative 2t containing two ketone functional groups selectively
underwent cycloalkenylation via the thermodynamic enolate, and
2v demonstrates selective cyclization with the axially disposed O-
Although cycloalkenylation to form fused ring systems was not
possible when -hydride elimination was a competing pathway,
bridged bicyclic ring systems such as bicyclo[3.3.1]nonanes (2r–t)
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 6
tethered alkene to give the a bicyclo[3.3.1]nonane rather than with
the all-carbon tethered alkene to give a bicyclo[3.2.1]octane.
The nickel-mediated cyclization was demonstrated to be
plausible by treatment of -bromo ketone 13 with a stoichiometric
quantity of Ni(cod)2. The low yield for this transformation may
reflect the importance of the specific ligand sphere accessed
through our catalytic manifold and emphasizes the synthetic utility
of our methodology. Taken together, these mechanistic
investigations highlight the possibility of both zinc and nickel to
mediate C–C bond formation between unstabilized enolates and
unactivated alkenes. Additional mechanistic investigations of the
roles of zinc and nickel are ongoing and will be reported in due
course.
1
2
3
4
5
6
7
8
Under the reported reaction conditions, all substrates were
completely selective for the exo-mode of cyclization and gave cis-
fused products. No alkene isomerization was observed for
9
We have effectively expanded allyl-metal catalysis for carbonyl
,-dehydrogenation from palladium to nickel, thereby allowing
for the use of a more sustainable and inexpensive first-row
transition metal catalyst. Furthermore, key limitations to the
substrate specificity and scope of the allyl-palladium-catalyzed
,-dehydrogenation conditions were overcome using the more
general nickel-catalyzed reaction conditions for the
dehydrogenation of ketones, nitriles, esters, and amides. The use of
allyl-nickel catalysis also enabled an oxidative cycloalkenylation
reaction between unstabilized ketone enolates and unactivated
alkenes, providing access to diverse bicyclic architectures and a
new retrosynthetic C–C bond disconnection for the synthesis of
complex polycyclic molecules.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website. Experimental procedures and spectroscopic
1
data for all new compounds including H- and 13C-NMR spectra
(PDF).
Figure 2. Mechanistic Investigations
AUTHOR INFORMATION
Corresponding Author
substrates that gave fused or bridged bicyclic products, which is an
advantage over previously reported palladium-mediated
cycloalkenylations of enoxysilanes, which gave isomeric mixtures
of alkenes.4
timothy.newhouse@yale.edu
ORCID: Timothy R. Newhouse: 0000-0001-8741-7236
We wanted to probe the identity of the metal responsible for C–
C bond formation between the ketone enolate and the pendant
olefin (Figure 2). Two mechanistic possibilities could be
envisioned: one involves the carbometalation of the pendant
alkene20 by a zinc enolate and the other involves the proposed
migratory insertion of an alkene to an allyl-nickel enolate. Under
the standard conditions, 1i underwent efficient alkenylation (Figure
2a). When substrate 1i was heated with Zn(TMP)2 and ZnBr2, we
found that the zinc-mediated cyclization was indeed possible, albeit
in low conversion. Subsequent quenching with D2O afforded the
fully saturated, deuterated species 12 in 32% yield with 68%
deuterium incorporation (Figure 2b) and suggests the intermediacy
of an alkylzinc intermediate. Related cyclizations of activated zinc
enolates with unactivated olefins have been reported.21
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We are grateful for financial support from Yale University, the
Sloan Foundation, Nalas Engineering, Amgen, the NSF (CAREER,
1653793), and the NIH-funded Chemistry/Biology Interface
Training Program (D.H., T32GM067543). Dr. Brandon Mercado is
gratefully acknowledged for X-ray crystallography of compound
SI-13.
REFERENCES
(1) (a) For a seminal report of nickel-catalyzed alkenylation of
enolates, see: Millard, A. A.; Rathke, M. W. A Nickel Catalyst for
the Arylation and Vinylation of Lithium Ester Enolates. J. Am.
Chem. Soc. 1977, 99, 4833–4835. (b) For a review on palladium-
and nickel-catalyzed -alkenylation via cross coupling, see:
Ankner, T.; Cosner, C.C.; Helquist, P. Palladium- and Nickel-
Catalyzed Alkenylation of Enolates. Chem. Eur. J. 2013, 19, 1858–
1871. (c) For a recent report of copper-catalyzed alkenylation of
zinc enolates employing iodonium salts, see: Liu, C.; Wang, Q.
Alkenylation of C(sp3)-H Bonds by Zincation/Copper-Catalyzed
Cross Coupling with Iodonium Salts. Angew. Chem. Int. Ed. 2018,
57, 4727–4731
Despite the possibility of a zinc-mediated cyclization, the
subsequent addition of nickel and allyl oxidant to effect
transmetalation and -hydride elimination of the alkylzinc species
did not provide a significant amount of alkenylation product 2i
(Figure 2c). Similarly, treatment of an alkylzinc intermediate
prepared from the corresponding alkyl bromide to identical allyl-
nickel conditions also provided low yields of alkenylation product
(see Supporting Information). These results suggest that while a
zinc-mediated anionic cyclization followed by an allyl-nickel-
mediated -hydride elimination is one possible mechanism for
cycloalkenylation, the migratory insertion of a nickel enolate
cannot be ruled out given additional experiments conducted in the
absence of zinc (Figure 2d).
(2) Ito, Y.; Aoyama, H.; Hirao, T.; Mochizuki, A.; Saegusa, T.
Cyclization Reactions via Oxo-π-allylpalladium(II) Intermediates.
J. Am. Chem. Soc. 1979, 101, 494–496.
ACS Paragon Plus Environment

Page 5 of 6
Journal of the American Chemical Society
(3) (a) Kende, A. S.; Roth, B.; Sanfilippo, S. J. Facile, Palladium(II)-
Dehydrogenation of Cyclohexanone to Cyclohexenone Catalyzed
by Pd(DMSO)2(TFA)2: Evidence for Ligand-Controlled
Chemoselectivity. J. Am. Chem. Soc. 2013, 135, 8205–8212.
(13) Chen, M.; Dong, G. Direct Catalytic Desaturation of Lactams
Enabled by Soft Enolization. J. Am. Chem. Soc. 2017, 139, 7757–
7760.
(14) Chen, M.; Rago, A.; Dong, G. Platinum-catalyzed Desaturation of
Lactams, Ketones and Lactones. Angew. Chem. Int. Ed. 2018, 57,
16205–16209.
Mediated Synthesis of Bridged and Spirocyclic Bicycloalkenones.
J. Am. Chem. Soc. 1982, 104, 1784–1785. (b) Kende, A. S.; Roth,
B.; Sanfilippo, P. J.; Blacklock, T. J. Mechanism and
1
2
3
4
5
6
7
8
Regioisomeric
Control
in
Palladium(II)-Mediated
Cycloalkenylations. A Novel Total Synthesis of (±)-Quadrone. J.
Am. Chem. Soc. 1982, 104, 5808–5810.
(4) (a) For a review on palladium-mediated cycloalkenylations, see:
LeBras, J.; Muzart, J. Base-free palladium-mediated
cycloalkenylations of olefinic enolic systems. Tetrahedron 2015,
71, 9035–9059. (b) Toyota, M.; Ihara, M. Development of
Palladium-Catalyzed Cycloalkenylation and its Application to
Natural Product Synthesis. Synlett 2002, 1211–1222.
(5) Dénès, F.; Pérez-Luna, A.; Chemla, F. Addition of Metal Enolate
Derivatives to Unactivated Carbon-Carbon Multiple Bonds. Chem.
Rev. 2010, 110, 2366–2447.
(15) (a) Ueno, S.; Shimizu, R.; Kuwano, R. Nickel-Catalyzed
Formation of a Carbon-Nitrogen Bond at the -Position of
Saturated Ketones. Angew. Chem. Int. Ed. 2009, 48, 4543–4545.
(b) Tutkowski, B. M.; Grigalunas, M.; Wiest, O.; Helquist, P. A
nickel-catalyzed ,-coupling of saturated ketones. Tetrahedron
Lett. 2015, 56, 3468–3472. (c) Jie, X.; Shang, Y.; Zhang, X.; Su,
W. Cu-Catalyzed Sequential Dehydrogenation–Conjugate
Addition for -Functionalization of Saturated Ketones: Scope and
Mechanism. J. Am. Chem. Soc. 2016, 138, 5623–5633. (d) Shang,
Y.; Jie, X.; Jonnada, K.; Zafar, S. N.; Su, W. Dehydrogenative
desaturation-relay via formation of multicenter-stabilized radical
intermediates. Nat. Commun. 2017, 8, 2273. (e) Li, H.; Jiang, Q.;
Jie, X.; Shang, Y.; Zhang, Y.; Goossen, L. J.; Su, W. Rh/Cu-
Catalyzed Ketone -Functionalization by Merging Ketone
Dehydrogenation and Carboxyl-Directed C-H Alkylation. ACS
Catal. 2018, 8, 4777–4782.
(16) Lee, K. L.; Ambler, C. M.; Anderson, D. R.; Boscoe, B. P.; Bree,
A. G.; Brodfuehrer, J. I.; Chang, J. S.; Choi, C.; Chung, S.; Curran,
K. J.; Day, J. E.; Dehnhardt, C. M.; Dower, K.; Drozda, S. E.;
Frisbie, R. K.; Gavrin, L. K.; Goldberg, J. A.; Han, S.; Hegen, M.;
Hepworth, D.; Hope, H. R.; Kamtekar, S.; Kilty, I. C.; Lee, A.; Lin,
L.-L.; Lovering, F. E.; Lowe, M. D.; Mathias, J. P.; Morgan, H. M.;
Murphy, E. A.; Papaioannou, N.; Patny, J. P.; Pierce, B. S; Rao, V.
R.; Saiah, E.; Samardjiev, I. J.; Samas, B. M.; Shen, M. W. H.;
Shin, J. H.; Soutter, H. H.; Strohbach, J. W.; Symanowicz, P. T.;
Thomason, J. R.; Trzupek, J. D.; Vargas, R.; Vincent, F.; Yan, J.;
Zapf, C. W.; Wright, S. W.Discovery of Clinical Candidate 1-
{[2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(6) Pei, T.; Wang, X.; Widenhoefer, R. A. Palladium-Catalyzed
Intramolecular Oxidative Alkylation of Unactivated Olefins. J.
Am. Chem. Soc. 2003, 125, 648–649.
(7) (a) Chen, Y.; Romaire, J. P.; Newhouse, T. R. Palladium-Catalyzed
,-Dehydrogenation of Esters and Nitriles. J. Am. Chem. Soc.
2015, 137, 5875–5878. (b) Chen, Y.; Turlik, A.; Newhouse, T. R.
Amide ,-Dehydrogenation Using Allyl-Palladium Catalysis and
a Hindered Monodentate Anilide. J. Am. Chem. Soc. 2016, 138,
1166–1169. (c) Zhao, Y.; Chen, Y.; Newhouse, T. R. Allyl-
Palladium Catalyzed ,-Dehydrogenation of Carboxylic Acids
via Enediolates. Angew. Chem. Int. Ed. 2017, 56, 13122–13125.
(d) Schuppe, A. W.; Huang, D.; Chen, Y.; Newhouse, T. R. Total
Synthesis of (–)-Xylogranatopyridine B via a Palladium-Catalyzed
Oxidative Stannylation of Enones. J. Am. Chem. Soc. 2018, 140,
2062–2066. (e) Szewczyk, S. M.; Zhao, Y.; Sakai, H. A.; Dube, P.;
Newhouse, T. R. ,-Dehydrogenation of esters with free O-H and
N-H functionalities with allyl-palladium catalysis. Tetrahedron
2018, 74, 3293–3300.
(8) For allyl-palladium-catalyzed dehydrogenation of ketones, see: (a)
Chen, Y.; Huang, D.; Zhao, Y.; Newhouse, T. R. Allyl-Palladium-
Catalyzed Ketone Dehydrogenation Enables Telescoping with
Enone ,-Vicinal Difunctionalization. Angew. Chem. Int. Ed.
2017, 56, 8258–8262. (b) Huang, D.; Zhao, Y. Newhouse, T. R.
Synthesis of Cyclic Enones by Allyl-Palladium-Catalyzed ,-
Dehydrogenation. Org. Lett. 2018, 20, 684–687.
methoxyisoquinoline-6-carboxamide (PF-06650833),
a Potent,
Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4
(IRAK4), by Fragment-Based Drug Design. J. Med. Chem. 2017,
60, 5521–5542.
(17) (a) Achonduh, G. T.; Hadei, N.; Valente, C.; Avola, S.; O’Brien,
C. J.; Organ, M. G. On the role of additives in alkyl–alkyl Negishi
cross-couplings. Chem. Commun. 2010, 46, 4109–4111. (b)
McCann, L. M.; Organ, M. C. On the Remarkably Different Role
of Salt in the Cross-Coupling of Arylzincs From That Seen with
Alkylzincs. Angew. Chem. Int. Ed. 2014, 53, 4386–4389.
(18) (a) Chen, K.; Ishihara, Y.; Galán, M. M.; Baran, P. S. Total
synthesis of eudesmane terpenes: cyclase phase. Tetrahedron
2010, 66, 4738–4744. (b) Thomas, A. F.; Ozainne, M.; Decorzant,
R.; Naf, F.; Lukacs, G. 10-Epijuneol, a new cis-eudesmane
sesquiterpenoid. Tetrahedron 1976, 32, 2261–2264. (c) Toyota,
M.; Asakawa, Y. An eudesmane-type sesquiterpene alcohol from
the liverwort Frulllania tamarisci. Phytochemistry 1990, 29,
3664–3665.
(19) (a) Presset, M.; Coquerel, Y.; Rodriguez, J. Syntheses and
Applications of Functionalized Bicyclo[3.2.1]octanes: Thirteen
Years of Progress. Chem. Rev. 2013, 113, 525–595. (b) Ruiz, M.;
López-Alvarado, P.; Giorgi, G.; Menéndez, J. C. Domino reactions
for the synthesis of bridged bicyclic frameworks: fast access to
bicyclo[n.3.1]alkanes. Chem. Soc. Rev. 2011, 40, 3445–3454.
(20) (a) Stadtmüller, H.; Lentz, R.; Tucker, C. E.; Stüdemann, T.;
Dörner, W.; Knochel, P. Palladium-Catalyzed Iodine-Zinc
Exchange Reactions. A New Palladium-Mediated Intramolecular
Carbozincation of Alkenes. J. Am. Chem. Soc. 1993, 115, 7027–
7028. (b) Meyer, C.; Marek, I.; Courtemanche, G.; Normant, J.-F.
Carbocyclization of Functionalized Zinc Organometallics. Synlett
1993, 266–268.
(9) (a) Tasker, S. Z.; Standley, E. A.; Jamison, T. F. Recent advances
in homogeneous nickel catalysis. Nature 2014, 509, 299–309. (b)
Zweig, J. E.; Kim, D. E.; Newhouse, T. R. Methods Utilizing First-
Row Transition Metals in Natural Product Total Synthesis. Chem.
Rev. 2017, 117, 11680–11752.
(10) Nokami, J.; Watanabe, H.; Mandai, T.; Kawada, M.; Tsuji, J. The
palladium-catalyzed Michael addition reaction of the ketone
enolates generated by the decarboxylation of allyl--keto
carboxylates under neutral conditions. Tetrahedron Lett. 1989, 30,
4829–4832.
(11) For reviews on carbonyl dehydrogenation, see: (a) Muzart, J. One-
Pot Syntheses of ,-Unsaturated Carbonyl Compounds through
Palladium-Mediated Dehydrogenation of Ketones, Aldehydes,
Esters, Lactones, and Amides. Eur. J. Org. Chem. 2010, 3779–
3790. (b) Stahl, S. S.; Diao, T. Oxidation Adjacent to C=X bonds
by Dehydrogenation. Comp. Org. Synth. 2014, 7, 178–212. (c)
Turlik, A.; Chen, Y.; Newhouse, T. R. Dehydrogenation Adjacent
to Carbonyls Using Palladium-Allyl Intermediates. Synlett 2016,
27, 331–336. (d) Iosub, A. V.; Stahl, S. S. Palladium-Catalyzed
Aerobic Dehydrogenation of Cyclic Hydrocarbons for the
Synthesis of Substituted Aromatics and Other Unsaturated
Products. ACS Catal. 2018, 6, 8201–8213. (e) Hirao, T. Synthetic
Strategy: Palladium-Catalyzed Dehydrogenation of Carbonyl
Compounds. J. Org. Chem. 2019, 84, 1687–1692.
(12) (a) Diao, T.; Stahl, S. S. Synthesis of Cyclic Enones via Direct
Palladium-Catalyzed Aerobic Dehydrogenation of Ketones, J. Am.
Chem. Soc. 2011, 133, 14566–14569. (b) Diao, T.; Wadzinski, T.
J.; Stahl, S. S. Direct aerobic ,-dehydrogenation of aldehydes
and ketones with a Pd(TFA)2/4,5-diazafluorenone catalyst. Chem.
Sci. 2012, 3, 887–891. (c) Diao, T.; Pun, D.; Stahl, S. S. Aerobic
(21) Pérez-Luna, A.; Botuha, C.; Ferreira, F.; Chemla, F.
Carbometalation of unactivated alkenes by zinc enolate
derivatives. New J. Chem. 2008, 32, 594–606.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 6
O
O
1
2
Ni
R
R
unactivated ketone and
alkene partners
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6
ACS Paragon Plus Environment