Direct β-Alkylation of Ketones and Aldehydes via Pd-Catalyzed Redox Cascade

Article abstract of DOI:10.1021/jacs.8b03530

We report a direct β-alkylation of ketones and aldehydes with simple alkyl bromides through a Pd-catalyzed redox-cascade strategy. The use of a Cu cocatalyst is important for improved efficiency. The reaction is redox-neutral, without the need for strong acids or bases. Both cyclic and acyclic ketones, as well as α-branched aldehydes, are suitable substrates for coupling with secondary and tertiary alkyl bromides. Concise formal synthesis of Zanapezil is achieved using this β-alkylation method.

Full text of DOI:10.1021/jacs.8b03530

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Communication
Direct #-Alkylation of Ketones and
Aldehydes via Pd-Catalyzed Redox Cascade
Chengpeng Wang, and Guangbin Dong
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 30 Apr 2018
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Direct βꢀAlkylation of Ketones and Aldehydes via PdꢀCatalyzed
Redox Cascade
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Chengpeng Wang and Guangbin Dong*
Department of Chemistry, University of Chicago, Chicago, Illinois 60637, United States
Supporting Information Placeholder
egy to βꢀalkylation, the use of alkyl halides as the electrophile
ABSTRACT: We report a direct βꢀalkylation of ketones and
constitutes significant difficulties. First, oxidative addition of
Pd(0) to alkyl halides is generally more difficult than to aryl halꢀ
ides.12 Second, the resulting alkylꢀPd(II) species are prone to βꢀ
hydrogen elimination rather than migratory insertion.13 The semiꢀ
nal work by Firmansjah and Fu shows that such an issue could be
addressed using a bulky NHC ligand, but it remains challenging to
use secondary or tertiary alkyl halides.14 Alternatively, besides a
twoꢀelectron oxidative addition, electronꢀrich Pd(0) is also known
to undergo a oneꢀelectron pathway, in which Pd(0) can abstract
the halogen atom from an alkyl halide to give a Pd(I)ꢀX species
and an alkyl radical.15 This process has appeared in several Pdꢀ
catalyzed atomꢀtransfer, cross coupling, and carbonylative reacꢀ
tions using alkyl halides as the substrate.16 For example,
Alexanian17, Zhou18, Gevorgyan19 and Fu20 recently demonstrated
this concept in elegant alkylꢀHeck reactions with attractive scopes
and synthetic applications.
aldehydes with simple alkyl bromides through a Pdꢀcatalyzed
redoxꢀcascade strategy. The use of a Cu coꢀcatalyst is important
for improved efficiency. The reaction is redoxꢀneutral, without the
need for strong acids or bases. Both cyclic and acyclic ketones, as
well as αꢀbranched aldehydes, are suitable substrates for coupling
with secondary and tertiary alkyl bromides. Concise formal synꢀ
thesis of Zanapezil is achieved using this βꢀalkylation method.
Alkylation of carbonyl compounds has been an important and
fundamental approach to form carbon−carbon bonds.1 Convenꢀ
tionally, treatment of ketones with strong bases followed by addiꢀ
tion of alkyl halides provides αꢀalkylated products. In contrast,
direct alkylation at the unactivated β position is much more chalꢀ
lenging.2 While the powerful directing group approach enables βꢀ
C−H functionalization of various carbonyl compounds,3 βꢀ
alkylation4 of ketones and aldehydes remains difficult; in addition,
the βꢀpositions of cyclic ketones are generally inaccessible via a
directing mode. Recently, MacMillan and coworkers disclosed an
elegant approach for βꢀalkylation via merging enamine and photoꢀ
redox catalysis, in which Michael acceptors, or ketones/imines
were employed as the alkyl source (Scheme 1A).5,6 More recently,
an efficient oneꢀpot βꢀalkylation protocol was developed by
Newhouse and coworkers through a sequence of Pdꢀcatalyzed
ketone dehydrogenation followed by conjugate addition of an
organocuprate nucleophile (Scheme 1B).7,8 We were motivated by
the convenience of using readily available simple alkyl halides as
the alkyl source, which could possibly enable a direct βꢀalkylation
of saturated carbonyl compounds in the absence of stoichiometric
oxidants or reductants. Herein, we describe our initial efforts toꢀ
ward the development of a redoxꢀneutral βꢀalkylation of ketones
and certain aldehydes with a weaker base and simple alkyl broꢀ
mides utilizing a palladiumꢀcatalyzed redoxꢀcascade strategy
(Scheme 1C).
Scheme 1. βꢀAlkylation of Aldehydes and Ketones
Our laboratory has been engaged in systematic development of a
Pdꢀredoxꢀcascade approach for βꢀfunctionalization of ketones9
and amides10. This strategy starts with Pd(II)ꢀenolate formation
between a Pd(II) precatalyst and the carbonyl substrate, followed
by βꢀhydrogen elimination to give an unsaturated carbonyl interꢀ
mediate.11 The resulting Pd(0) species then undergoes oxidative
addition with the electrophile, e.g. an aryl halide, to give an arylꢀ
Pd(II) intermediate, which upon migratory insertion and protonaꢀ
tion of the new Pd(II)ꢀenolate provides the βꢀproduct and regenerꢀ
ates the Pd(II) catalyst. As a result, the electrophile serves as both
the oxidant for carbonyl desaturation and the carbon source for βꢀ
functionalization. However, to extend this Pdꢀredoxꢀcascade stratꢀ
For the proposed βꢀalkylation pathway (Scheme 2), it is possible
to trigger the same radical formation from an alkyl halide with the
electronꢀrich Pd(0) species, which could be followed by a radical
relay with the enone intermediate and then recombination of the
αꢀradical with the Pd(I)ꢀX to generate the βꢀalkylated Pd(II) enoꢀ
late. However, the key difference between this proposed reaction
and the Pd(I)ꢀmediated alkylꢀHeck reaction is that at any given
time only a catalytic amount of enone exists in this system. As a
consequence, if the generated unstabilized alkyl radical species
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cannot react with the enone in a timely fashion, many side reacꢀ
yields (Table S1, entries 4–8). The role of Cs2CO3 was proposed
to first neutralize the HBr generated in the reaction and second
serve as a halide scavenger due to the low solubility of CsBr,
while other bases were less effective (Table S1, entries 9–11).
Finally, it is interesting to note that a catalytic amount of HOAc
was also crucial, though the exact reason is unclear (Table S1,
entries 12 and 13).
tions would occur, e.g. C−H abstraction and dimerization. Moreoꢀ
ver, whether the Pdꢀcatalyzed twoꢀelectron dehydrogenation proꢀ
cess would be compatible in the presence of reactive radical speꢀ
cies could be another concern.
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Scheme 2. The Proposed Strategy
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Table 1. Selected Optimization of Reaction Conditionsa
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We anticipated that the main issue of the proposed catalytic cyꢀ
cle (Scheme 2) should come from the instability of the alkyl radiꢀ
cal generated, thus hypothesized that, by adding an additional
catalyst, e.g. a Cu salt, that can reversibly generate the alkyl radiꢀ
cal,21 the lifetime of the alkyl radical could be significantly exꢀ
tended. In addition, the αꢀradical generated after conjugate addiꢀ
tion could possibly recombine with Cu(I) (instead of Pd(I)) to
give a Cu(II) enolate, which may minimize potential undesired βꢀ
hydrogen elimination prior to the enolate protonation; the Pd(I)
species could then be oxidized by Cu(II) to regenerate the Pd(II)
catalyst. To test the hypothesis, cyclohexanone (1a) and 2ꢀ
bromopropane (2a) were employed as the model substrates; gratiꢀ
fyingly, the desired βꢀalkylation product (3a) was obtained in
65% yield (Table 1, entry 1) using Pd(OAc)2/P(iꢀPr)3/Cu(OPiv)2
as the catalysts. In this reaction, no αꢀalkylation product was obꢀ
served. The overꢀdehydrogenation product (3ꢀisopropylꢀ2ꢀ
cyclohexenone), generated via further βꢀhydrogen elimination of
the βꢀalkylated Pdꢀenolate, was only observed in a small amount
(<3%) in this case. A high concentration of the ketone substrate
appeared to be necessary to maintain fast dehydrogenation; when
the ketone and the alkyl bromide were used in a 1:1 ratio, lower
efficiency was observed under the current conditions (Table 1,
entry 2).
aUnless otherwise noted, all the reactions were run with 1a (1.0
mmol) and 2a (0.4 mmol) in 0.44 mL solvent for 18 h. NMR
b
yield determined using 1,1,2,2ꢀtetrachloroethane as the internal
c
standard. 3,5ꢀDiꢀalkylation and overꢀdehydrogenation products
were observed in 9% and 4% yields, respectively.
The scope of alkyl halides was first investigated with cyclohexaꢀ
none and propiophenone (Scheme 3).23 A wide range of secondꢀ
ary and tertiary alkyl bromides were suitable substrates for this
transformation.24 Besides isopropyl bromide (3a, 3i), cyclic alkyl
bromides, ranging from 4ꢀ to 8ꢀmembered rings, smoothly delivꢀ
ered the desired products in moderate to good yields (3b–3g).
Attributed to the nearꢀneutral reaction conditions, acid- or base-
reactive functional groups were well tolerated, including ethers
(3e), Bocꢀprotected amines (3j), esters (3l–3p), nitriles (3o), cyꢀ
clopropane moieties (3p), benzoylꢀ, TBSꢀ and MOMꢀprotected
alcohols (3l, 3q, 3r), amides (3w), electronꢀrich olefins (3u) and
ketones (3v).25 2ꢀBromonorbornane gave the alkylation at the exo
face of norbornane (3k), which was confirmed by Xꢀray crystalꢀ
lography. Tertiary alkyl bromides also worked well for both cyꢀ
clic and linear ketones (3h, 3s, 3t), but the overꢀdehydrogenation
became somewhat competitive. A oneꢀpot hydrogenation protocol
could be adopted to ease the isolation. Alkyl bromides derived
from bioactive natural products, such as cholesterol (3u), androsꢀ
terone (3v), pentoxyphylline (3w), and αꢀtocopherol (3x), also
smoothly afforded the desired coupling products. Interestingly,
when propiophenone was used as substrates (Scheme 3B), the
ortho C−H bonds on the aryl group remained intact. It is noteworꢀ
thy that the reductive deꢀbromination of alkyl bromides was found
to be the major side reaction that accounts for the mass balance of
this transformation (see Table S2 for details).
A number of control experiments were then conducted to underꢀ
stand the role of each reactant (Tables 1 and S1). First, a compaꢀ
rable yield was obtained when the reaction was performed in the
dark (Table 1, entry 3), suggesting that light is not needed for the
radical generation in this reaction. Both alkyl iodides and chloꢀ
rides were less efficient than the corresponding alkyl bromide
(Table 1, entries 4 and 5). Unsurprisingly, no product was detectꢀ
ed without palladium (Table 1, entry 6), and the ligand played a
pivotal role in this transformation (Table 1, entries 7–10). P(iꢀPr)3
was optimal due to its electronic richness and proper steric bulkiꢀ
ness. Though PCy3 was still effective, bulkier P(tꢀBu)3 or less
electronꢀrich PPh3 gave much lower yields. In addition, bidentate
ligands were not efficient (Table S1, entries 2 and 3). Adding
Cu(OPiv)2 coꢀcatalyst was found to significantly improve the
yield from 20% to 65% (Table 1, entry 11).22 Meanwhile, lowerꢀ
ing the Cu loading, using Cu(OAc)2 instead, or switching to Cu(I)
precatalyst only slightly reduced the yield (Table 1, entries 12–
14). A mixed solvent between benzene and MeOAc proved to be
optimal, though benzene alone or 1,4ꢀdioxane also gave similar
Scheme 3. Substrate Scope of Alkyl Bromides
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O
O
Scheme 4. Substrate Scope of Ketones and Aldehydes
'standard' conditions
+
Alkyl Br
1
2
Alkyl
3a-x
1a-b
2a-x
3
4
A. Scope with cyclohexanone 1a
O
O
O
O
5
6
7
8
Me
Me
, 63%
3c
, 63%
3d
3b
, 51%
, 41%
3a
O
O
O
O
9
10
11
12
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O
3e
3f
3g
3h
, 53%
, 56%
, 54%
, 54%
B. Scope with propiophenone 1ba
intact
O
O
H
O
Ph
Me
Me
Ph
N
Boc
H
3i, 51%
3j, 64%
3k, 55% (d.r. > 20:1)
from exo R-Br
X-ray for the DNP-
3k
hydrazone of
CN
O
O
O
O
O
O
Ph
Ph
Ph
Ph
Ph
O
O
CO2Me
CO2Me
Me
O
Me
Me
3m
Me
O
3l
3n
3o
, 54% (64% brsm)
, 68%
, 64%
, 56%
O
O
O
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
OBz
O
OTBS
OMOM
Me
Me
Me
O
Me
3q
Me
b
b
3p
3r
, 63%
, 65%
, 61%
3s
3t
, 55% (69% )
, 57% (77% )
Me
Me
b
Me
aIn these cases, 5 equiv of ketone or aldehyde was used. Yield
O
Me
O
Ph
O
Me
Me
in the parentheses was obtained when a oneꢀpot hydrogenation
was conducted after the reaction. The product was isolated as an
H
Me
H
N
N
c
O
Ph
Me
H
O
Ph
H
H
N
Me
O
N
H
H
alcohol after NaBH4 reduction.
H
Me
The synthetic utility of this method is illustrated in a concise
formal synthesis of Zanapezil, a selective acetylcholinesterase
inhibitor (Scheme 5).26 Employing ketone 6 and bromide 7 as the
coupling partners, a convergent synthesis was achieved through βꢀ
alkylation. While 3 equiv of ketone 6 was used for higher effiꢀ
ciency, most unreacted ketones can be easily recovered. Overall,
this method offers a new bond disconnection strategy for the synꢀ
thesis of Zanapezil.
3v, 41% (63% brsm)c
(d.r. = 2.1:1)
3w, 50%
c
3u
, 48% (61% brsm)
(d.r. = 1.6:1)
from equatorial R-Br
from axial R-Br
O
Me
Me
O
Ph
Me
Me
Me
Me
Me
Me Me
Me
O
3x, 58%
aIn these cases, 5 equiv of 1b was used. bYield in the parentheses
was obtained when a oneꢀpot hydrogenation was conducted after
the reaction. 15 mol% Pd(OAc)2, 30 mol% P(iꢀPr)3 HBF4 and 30
mol% Cu(OPiv)2 were used.
Scheme 5. Formal Synthesis of Zanapezil
c
.
The scope of the carbonyl substrates was further explored
(Scheme 4). Cyclic ketones, such as cyclopentanone (5a), polyꢀ
substituted cyclohexanones (5b and 5c), and benzocyclohepꢀ
tanone (5d), were competent substrates. The 1,4ꢀdiketone also
yielded the desired product (5e). Simple linear ketones, e.g. 3ꢀ
pentanone (5f) and 2ꢀbutanone (5g), exhibited higher reactivity. In
addition, propiophenones with trifluoromethyl or methoxy subꢀ
stituents at the para position afforded the desired βꢀalkylation
products in good yields (5h, 5i). Intriguingly, aldehydes with αꢀ
branches were also feasible substrates under the identical reaction
conditions (5j–5m). The αꢀsubstituents were important to prevent
selfꢀaldol condensation reactions. Nevertheless, both secondary
and tertiary alkyl bromides could effectively couple with αꢀarylꢀ
or alkylꢀsubstituted aldehydes. In particular, the aldehyde containꢀ
ing a cyclic structure gave predominately the transꢀproduct (5m).
Finally, to probe the radical participation in this reaction, a radiꢀ
cal clock experiment was conducted (eq. 2). When alkyl bromide
10 with a tethered triꢀsubstituted olefin was subjected to the reacꢀ
tion conditions with or without Cu coꢀcatalyst, ketone 11 was
obtained as the only product in which the 5ꢀexo cyclization proꢀ
ceeded prior to the 1,4ꢀaddition.27 This observation is consistent
with the proposed radicalꢀinvolved mechanism, as the cyclization
would be sluggish for the alternative oxidative addition/migratory
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D. W. C. J. Am. Chem. Soc. 2014, 136, 6858. (c) Jeffrey, J. L.; Petroniꢀ
insertion pathway due to the steric hindrance of the olefin. Addiꢀ
tionally, an enantioenriched alkyl bromide (S)ꢀ2l with 90% ee
delivered the racemic alkylation product, which also indicates
alkyl radicals to be reasonable intermediates (eq. 3).
jević, F. R.; MacMillan, D. W. C. J. Am. Chem. Soc. 2015, 137, 8404.
(6) For βꢀalkylation of cyclopentanones using a tungsten photoꢀredox
catalyst, see: Okada, M.; Fukuyama, T.; Yamada, K.; Ryu, I.; Ravelli, D.;
Fagnoni, M. Chem. Sci. 2014, 5, 2893.
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9
(7) Chen, Y.; Huang, D.; Zhao, Y.; Newhouse, T. R. Angew. Chem. Int.
Ed. 2017, 56, 8258.
(8) For examples of using such a strategy to introduce other functional
groups, see: (a) Hayashi, Y.; Itoh, T.; Ishikawa, H. Angew. Chem. Int. Ed.
2011, 50, 3920. (b) Zhang, S.ꢀL.; Xie, H.ꢀX.; Zhu, J.; Li, H.; Zhang, X.ꢀS.;
Li, J.; Wang, W. Nat. Commun. 2011, 2, 211. (c) Jie, X.; Shang, Y.;
Zhang, X.; Su, W. J. Am. Chem. Soc. 2016, 138, 5623.
(9) (a) Huang, Z.; Dong, G. J. Am. Chem. Soc. 2013, 135, 17747. (b)
Huang, Z.; Sam, Q. P.; Dong, G. Chem. Sci. 2015, 6, 5491. (c) Huang, Z.;
Dong, G. Tetrahedron 2018, DOI: 10.1016/j.tet.2018.03.017.
(10) (a) Chen, M.; Dong, G. J. Am. Chem. Soc. 2017, 139, 7757. (b)
Chen, M.; Liu, F.; Dong, G. Angew. Chem. Int. Ed. 2018, 57, 3815.
(11) For recent examples of Pdꢀcatalyzed direct dehydrogenation of keꢀ
tones, see: (a) Diao, T.; Stahl, S. S. J. Am. Chem. Soc. 2011, 133, 14566.
(b) Gao, W.; He, Z.; Qian, Y.; Zhao, J.; Huang, Y. Chem. Sci. 2012, 3,
883. (c) Diao, T.; Wadzinski, T. J.; Stahl, S. S. Chem. Sci. 2012, 3, 887.
(d) Diao, T.; Pun, D.; Stahl, S. S. J. Am. Chem. Soc. 2013, 135, 8255.
(12) (a) Collman, J. P. Acc. Chem. Res. 1975, 8, 342. (b) Pearson, R.
G.; Figdore, P. E. J. Am. Chem. Soc. 1980, 102, 1541.
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In summary, we have developed a new method for direct βꢀ
alkylation of simple ketones and αꢀbranched aldehydes via Pdꢀ
catalyzed redox cascade. Different from existing βꢀ
functionalization methods, this strategy permits the use of simple,
readily available alkyl bromides as the alkylation source. Considꢀ
ering the relatively broad substrate scope, the redoxꢀneutral feaꢀ
ture, and high functional group tolerance, this approach should
find use in complex molecule synthesis. In addition, merging a
radical process with Pdꢀcatalyzed desaturation should also have
implications beyond this work. Efforts on further improving the
reaction efficiency and enabling enantioselective transformations
are ongoing.
(13) Ozawa, F.; Ito, T.; Yamamoto, A. J. Am. Chem. Soc. 1980, 102,
6457.
(14) Firmansjah, L.; Fu, G. C. J. Am. Chem. Soc. 2007, 129, 11340.
(15) Kramer, A. V.; Osborn, J. A. J. Am. Chem. Soc. 1974, 96, 7832.
(16) For a review on Pdꢀcatalyzed radicalꢀinvolved various transforꢀ
mations, see: Liu, Q.; Dong, X.; Li, J.; Xiao, J.; Dong, Y.; Liu, H. ACS
Catal. 2015, 5, 6111
(17) (a) Bloome, K. S.; Alexanian, E. J. J. Am. Chem. Soc. 2010, 132,
12823. (b) Bloome, K. S.; McMahen, R. L.; Alexanian, E. J. J. Am. Chem.
Soc. 2011, 133, 20146. (c) McMahon, C. M.; Alexanian, E. J. Angew.
Chem. Int. Ed. 2014, 53, 5974. (d) Venning, A. R. O.; Kwiatkowski, M.
R.; Peña, J. E. R.; Lainhart, B. C.; Guruparan, A. A.; Alexanian, E. J. J.
Am. Chem. Soc. 2017, 139, 11595.
ASSOCIATED CONTENT
Supporting Information Experimental procedures; spectral
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
(18) Zou, Y.; Zhou, J. Chem. Commun. 2014, 50, 3725.
(19) (a) Parasram, M.; Iaroshenko, V. O.; Gevorgyan, V. J. Am. Chem.
Soc. 2014, 136, 17926. (b) Kurandina, D.; Parasram, M.; Gevorgyan, V.
Angew. Chem. Int. Ed. 2017, 56, 14212. (c) Kurandina, D.; Rivas, M.;
Radzhabov, M.; Gevorgyan, V. Org. Lett. 2018, 20, 357.
(20) Wang, G.ꢀZ.; Shang, R.; Cheng, W.ꢀM.; Fu, Y. J. Am. Chem. Soc.
2017, 139, 18307.
(21) Boyer, C.; Corrigan, N. A.; Jung, K.; Nguyen, D.; Nguyen, T.ꢀK.;
Adnan, N. N. M.; Oliver, S.; Shanmugam, S.; Yeow, J. Chem. Rev. 2016,
116, 1803.
(22) For an example of using a copper coꢀcatalyst to improve the effiꢀ
ciency in Pdꢀcatalyzed radicalꢀinvolved reactions, see: Feng, Z.; Min, Q.ꢀ
Q.; Xiao, Y.ꢀL.; Zhang, B.; Zhang, X. Angew. Chem. Int. Ed. 2014, 53,
1669.
(23) The overꢀdehydrogenation byproduct formation for linear ketones
was easier due to the higher propensity of βꢀhydrogen elimination caused
by the flexibility of the skeleton, but fortunately, the product/byproduct
ratio was greater than 10:1 for most cases.
AUTHOR INFORMATION
Corresponding Author
*gbdong@uchicago.edu
ORCID
Guangbin Dong: 0000ꢀ0003ꢀ1331ꢀ6015
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank University of Chicago and Eli Lilly for research supꢀ
ports. Mr. KiꢀYoung Yoon is thanked for Xꢀray crystallography.
Dr. Ming Chen is acknowledged for checking the experiments.
We also thank Chiral Technology for donation of chiral HPLC
columns.
(24) Primary alkyl bromides are potentially viable substrates, but they
suffer from low reaction rates and undesired SN2 reactions with acetate or
pivalate salts. The following reaction delivered the desired product in 12%
yield.
REFERENCES
(1) Modern Carbonyl Chemistry; Otera, J., Ed.; WileyꢀVCH: Weinꢀ
heim, 2000.
(2) Huang, Z.; Dong, G. Acc. Chem. Res. 2017, 50, 465.
(3) For a recent review, see: Huang, Z.; Dong, G. Tetrahedron Lett.
2014, 55, 5869.
(4) For selected examples of βꢀalkylation of amides with a DG apꢀ
proach, see: (a) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2010, 132,
3965. (b) Zhang, S.ꢀY.; He, G.; Nack, W. A.; Zhao, Y.; Li, Q.; Chen, G. J.
Am. Chem. Soc. 2013, 135, 2124. (c) Wu, X.; Zhao, Y.; Ge, H. J. Am.
Chem. Soc. 2014, 136, 1789. (d) Chen, K.; Shi, B.ꢀF. Angew. Chem. Int.
Ed. 2014, 53, 11950.
(25) For 3v, a small amount of dehydrogenation product of the cycloꢀ
pentanone moiety was observed (<5%).
(26) Ishihara, Y.; Hirai, K.; Miyamoto, M.; Goto, G. J. Med. Chem.
1994, 37, 2292.
(27) Peacock, D. M.; Roos, C. B.; Hartwig, J. F. ACS Cent. Sci. 2016,
2, 647.
(5) (a) Petronijević, F. R.; Nappi, M.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2013, 135, 18323. (b) Terrett, J. A.; Clift, M. D.; MacMillan,
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