Allyl-Palladium-Catalyzed Ketone Dehydrogenation Enables Telescoping with Enone α,β-Vicinal Difunctionalization

Article abstract of DOI:10.1002/anie.201704874

The telescoping of allyl-palladium catalyzed ketone dehydrogenation with organocuprate conjugate addition chemistry allows for the introduction of aryl, heteroaryl, vinyl, acyl, methyl, and other functionalized alkyl groups chemoselectively to a wide variety of unactivated ketone compounds via their enone counterparts. The compatibility of the dehydrogenation conditions additionally allows for efficient trapping of the intermediate enolate with various electrophiles. The utility of this approach is demonstrated by comparison to several previously reported multistep sequences.

Full text of DOI:10.1002/anie.201704874

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Allyl-Palladium Catalyzed Ketone Dehydrogenation Enables
Telescoping with Enone Alpha,Beta-Vicinal Difunctionalization
Authors: Yifeng Chen, David Huang, Yizhou Zhao, and Timothy R.
Newhouse
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201704874
Angew. Chem. 10.1002/ange.201704874
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10.1002/anie.201704874
Angewandte Chemie International Edition
COMMUNICATION
Allyl-Palladium Catalyzed Ketone Dehydrogenation Enables
a,b
Telescoping with Enone
-Vicinal Difunctionalization
Yifeng Chen, David Huang†, Yizhou Zhao†, Timothy R. Newhouse*
Abstract: The telescoping of allyl-palladium catalyzed ketone
a. Pd-catalyzed β-arylation:
dehydrogenation with organocuprate conjugate addition chemistry
ArX
or
MesArIOTf
O
O
O
allows for the introduction of aryl, heteroaryl, vinyl, acyl, methyl, and
H
cat. [Pd]
other functionalized alkyl groups chemoselectively to a wide variety
of unactivated ketone compounds via their enone counterparts. The
Ar
compatibility of the dehydrogenation conditions additionally allows
for efficient trapping of the intermediate enolate with various
electrophiles. The utility of this approach is demonstrated by
comparison to several previously reported multistep sequences.
b. Cu-catalyzed β-functionalization:
O
O
O
cat. [Cu]
NuH
Ph
Nu
Ph
Ph
H
Nu = OR, NR2, HC(COR)2
c. This work:
O
The α,β-vicinal difunctionalization of enones is a standard
tactic in organic synthesis utilized for the programmable,
multicomponent assembly of readily available materials in a
single synthetic step.[1] While enone starting materials can be
prepared from saturated ketones by a number of different
methodologies,[2] it would be advantageous to instead use the
more inexpensive and readily available ketone oxidation state
directly for α,β-vicinal difunctionalization in order to avoid
discrete preparation and isolation of the enones in a separate
synthetic operation.[3]
O
O
CuLn
E+
E
R
R
Base
cat. [Pd]
allyl oxidant
then
Figure 1. Development of Telescoped Ketone Dehydrogenation and a,b-
Vicinal Difunctionalization.
approaches.[2] Furthermore, this dehydrogenation can be
organocuprate-mediated
difunctionalization of the intermediate enones (Figure 1c).
telescoped
with
α,β-vicinal
While functionalization of acyclic carbonyl compounds at the
β-position has been made possible by directed C-H activation,
especially with palladium catalysis,[4] derivatization of cyclic
ketones by this same approach is geometrically challenging.
Instead, methods to obtain cycloalkanones with the β-position
functionalized[5] have either relied on multistep sequences or
more recently by conversion of ketones to activated
intermediates such as enamines that can undergo oxidation to
an allylic radical species[6] or enones that can undergo conjugate
addition.[7,8] Through the use of palladium catalysis, Dong and
co-workers were able to functionalize in situ generated enone
intermediates with aryl halides[7a] or diaryliodonium salts[7b] to
provide β-arylated ketones (Figure 1a). Su and co-workers
reported the addition of latent, stabilized nucleophiles, including
malonates and sulfonamides, to enone intermediates generated
from propiophenone derivatives by a copper-catalyzed oxidation
(Figure 1b).[7c] Despite these advances, a method has not yet
emerged that is applicable to unactivated, complex ketone
starting materials, nor has a strategy been reported for the
addition of unstabilized nucleophiles to modestly electrophilic
enone intermediates.
Although organocuprates have been widely used for 1,4-
addition due to their ease of preparation and their high degree of
functional group compatibility, the basic and anhydrous
conditions of organocuprate reactions have precluded
telescoping[9] with the most efficient and widely-used
dehydrogenation methods,[2] many of which require incompatible
acidic or polar aprotic solvents. It was hypothesized that if our
previously reported conditions for carboxylic acid derivative
dehydrogenation[10] could be adapted for the dehydrogenation of
ketones, organocuprates could then be added to the same pot
i) Zn(TMP)2, toluene, 0 oC;
2.5 mol% [Pd(allyl)Cl]2,
O
O
Me
Me
diethyl allyl phosphate,120 o
C
Me
Me
ii) Me2CuMgBr•SMe2, THF,
HMPA, MeI, -78 to 23 oC
Me
1a
Me
4a
Me
Me
Me
i-Pr
Me Me
Zn
Me Me
Me
Me
Me
Me
Cy
N
N
N
N
Li
i-Pr
Li
Me
In this report, the one-step dehydrogenation of classically
challenging ketones is made possible through the use of allyl-
palladium catalysis by way of a zinc enolate, which may reduce
the dependency on two-step ketone dehydrogenation
Zn(TMP)2
LiTMP
LiCyan
entry
yield (%) [a]
variation from standard conditions
63[b] (80)
53 (76)
10 (33)
0 (29)
1
2
3
4
5
none
THF, 100 °C
LiTMP, ZnCl2
LiCyan, ZnCl2
allyl acetate
[*]
[†]
Dr. Y. Chen, D. Huang, Y. Zhao, Prof. Dr. T. R. Newhouse
Department of Chemistry, Yale University
225 Prospect Street, PO Box 208107, New Haven, CT, 06511
E-mail: timothy.newhouse@yale.edu
6 (11)
Figure 2. Optimization of Telescoped Ketone Dehydrogenation and a,b-
Vicinal Difunctionalization.
[a]
1H-NMR yield was determined using 1,3,5-trimethoxybenzene as an
D.H. and Y.Z. contributed equally to this work.
internal standard. 1H-NMR yield of the enone intermediate is indicated in
parentheses. [b] Isolated yield.
Supporting information for this article is given via a link at the end of
the document
The author(s) of this article can be found under:
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10.1002/anie.201704874
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COMMUNICATION
Table 1. Scope of Ketones and Nucleophiles for Telescoped Ketone Dehydrogenation and Conjugate Addition.[a,b]
O
O
O
3
R
CuLn
Zn(TMP)2
2.5 mol% [Pd(allyl)Cl]2
OP(OEt)2
then H+
R
1
2
a. vinyl and (hetero)aryl nucleophiles
c. alkyl nucleophiles
Me
O
H
Me
H
Me
O
O
O
Me
Me
H
H
Me
Me
H
Me
Me
Me
H
Me
O
Me
Me
H
O
O
O
H
TBSO
Me
Me
3s[d] (60%)
Me
(i-Pr)2N
3a[c] (65%)
3b[c] (52%)
3c[c] (42%)
3t[d] (70%)
3u[c] (42%)
O
Me
Me
O
H
H
Me
O
Me
Me
Me
H
Me
H
H
Me
Me
H
O
OMOM
n-Bu
Me
H
H
Me
O
N
H
H
H
Me
Et
MOMO
Me
Me
Me
O
Et
H
Me
3v[c] (54%)
3w[c] (60%)
3x[c] (75%, 3:1 dr)
3d[d] (46%)
3e[c] (71%)
3f[d] (51%)
F
H
Me
Me
O
O
H
O
Me
O
H
Me
Me
Me
H
Me
OMOM
Me
Me
i-Pr
Me
N
Me
O
H
O
O
O
H
Me
H
N
O
Me
OMe
O
3g[d] (53%, 1:1 dr)
3h[d] (46%, 16:1 dr)
3i[d] (54%)
3y[c] (84%)
3z[c] (62%)
3aa[c] (38%)
O
O
Me
Me
O
O
O
Me
Me
Me
H
H
H
O
Me
O
Me
H
H
H
H
TBSO
H
H
Me
S
Me
3j[d] (49%)
TMS
MeO
MeO
MeO
3k[d] (70%)
3l[d] (59%)
3ab[c] (51%)
3ac[c] (72%)
3ad[c] (53%)
b. acyl nucleophiles
O
O
O
O
O
O
Me
Me
TMS
Me
CO2Et
O
n-Bu
Me
Et
Me
n-Bu
TBSO
Me
t-Bu
3ae[c] (45%)
O
Me
O
Me
3ag[f] (68%)
O
O
3af[c] (54%, 10:1 dr)
3m[e] (52%)
3n[e] (70%)
3o[e] (66%, 2:1 dr)
Cl
Me
Me
O
O
O
O
n-Bu
Me
H
t-Bu
Ph
H
Me
Me
H
CO2Me
CN
n-Bu
Me
Me
H
H
Me
Me
Me
O
O
O
MeO
O
H
3p[e] (47%, 2:1 dr)
3q[e] (54%)
3r[e] (74%)
3ah[f] (52%)
Me
3ai[f] (86%)
Me
[a] Reaction conditions: 1 (1.0 equiv), Zn(TMP)2 (1.0 equiv), toluene (0.4 M), 0 oC, 10 min, then [Pd(allyl)Cl]2 (2.5 mol%), diethyl allyl phosphate (1.0 equiv), 120
oC, 2 h; RCuLn (2.0 - 3.0 equiv), –78 to 23 oC, 12 h. [b] Isolated yield. [c] Organocuprates were derived from Grignard reagents. [d] Organocuprates were derived
from organolithium reagents. [e] Organocuprates were derived from metal aldimine reagents. [f] Organocuprates were derived from Negishi reagents.
because dehydrogenation proceeds under basic conditions,
uses a nonpolar solvent, and generates stoichiometric propene
as the only oxidation byproduct.
To test this hypothesis, we chose (+)-nopinone (1a) as the
model ketone substrate as it is a privileged chiral pool starting
material,[11,12] and dehydrogenation to form (+)-apoverbenone
relies on two-step solutions involving α-bromination followed by
elimination of HBr.[13] Through considerable optimization, we
found that successful ketone dehydrogenation requires the
specific combination of Zn(TMP)2,[14] a commercial homoleptic
zinc amide as base, and diethyl allyl phosphate as oxidant
(Figure 2).[15] These conditions allowed us to access the oxidized
enone product of 1a in 70% isolated yield. We then explored the
feasibility of telescoping the newly developed ketone
dehydrogenation conditions with established organocuprate
chemistry by sequentially adding
a nucleophile and an
electrophile to the same pot without work-up or isolation.
Gratifyingly, we found that the introduction of the methyl Gilman
reagent followed by hexamethylphosphoramide (HMPA) and
methyl iodide afforded ketone 4a in 63% isolated
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COMMUNICATION
Table 2. Scope of Ketones, Nucleophiles, and Electrophiles for Telescoped Ketone Dehydrogenation and a,b-Vicinal Difunctionalization.[a,b]
O
O
O
E
R
CuLn
E+
R
Zn(TMP)2
2.5 mol% [Pd(allyl)Cl]2
OP(OEt)2
then
4
1
2
O
Me
H
O
Me
H
H
Me
H
Me
O
O
O
Me
Me
Me
Me
Me
H
Me
H
Me
O
Me
H
H
Me
H
Et
Et
CO2Et
Me
Me
Me
MeO
Me
MOMO
t-Bu
4a[c] (64%)
4b[c] (41%, 10:1 dr)
4c[c] (56%)
4d[c] (52%)
4e[c] (40%, 7:1 dr)
4f[c] (54%)
[Gram Scale]
O
Me
H
O
O
O
Me
O
Me
Me
Me
H
OH
Me
OH
Me
CF3
Me
O
Me
CO2Et Me
Me
H
TBSO
Me
Me
Me
CF3
Me
Me
Me
Me
4k[d] (66%)
n-Bu
OH
4l[d] (71%, 6:1 dr)
4g[c] (55%)
4h[c] (47%)
4i[c] (46%)
4j[d] (65%)
[a] Reaction conditions: 1 (1.0 equiv), Zn(TMP)2 (1.0 equiv), toluene (0.4 M), 0 oC, 10 min, then [Pd(allyl)Cl]2 (2.5 mol%), diethyl allyl phosphate (1.0 equiv), 120
oC, 2 h; RCuLn (2.0 equiv), –78 to 23 oC, 3 - 6 h; then electrophile. [b] Isolated yield. [c] Organocuprates were derived from Grignard reagents. [d]
Organocuprates were derived from organolithium reagents.
yield (entry 1). When the reaction was conducted on a one-gram
scale, the product was obtained without any erosion in yield
(64%). Decreased yields were obtained when our previously
isopropyl (3y), cyclopropyl (3z), cyclopentyl (3aa, 3ab) and
cyclohexyl (3ac) functionality. The telescoped process also
tolerated acid-sensitive functional groups, thereby allowing for
the formation of products 3u and 3aa. The functional group
disclosed transmetallation procedures were employed: LiTMP
[10a]
with ZnCl2
provided product 4a in 10% yield while the use of
compatibility
demonstrated through the installation of an acetal containing
nucleophile (3af). The use of organozinc-derived
of
Grignard-derived
organocuprates
was
[10b]
LiCyan and ZnCl2
was ineffective (entries 2-4). Employment
of diethyl allyl phosphate as an oxidant was also critical for this
transformation as use of allyl acetate as an oxidant only
provided trace quantities of the product (entry 5).
organocuprates allowed for even greater functional group
compatibility and was highlighted through the synthesis of
products containing electron-withdrawing groups such as an
ester (3ag), nitrile (3ah), and chloride (3ai).
Under the optimized conditions, both vinyl and isopropenyl
nucleophiles were diastereoselectively introduced to various
ketones and afforded compounds 3a – 3c in moderate to good
yields. Analogous to our previous report, the use of allyl-
palladium catalysis allowed for the dehydrogenation of
substrates containing readily oxidizable functionality, such as a
tertiary amine (3b). The introduction of heterocycles was also
tolerated, as demonstrated by the products containing pyridine
(3f – 3h), furan (3i, 3j), benzofuran (3k), and thiophene (3l)
functionality. Furthermore this method readily provided the
protected enone 3i and represents a strategy to functionalize a
synthetic equivalent of cyclopentadienone, an anti-aromatic and
unstable compound.[16]
To test the robustness of our methodological approach, we
explored whether infrequently used metallated aldimines,[17]
generated by the insertion of an organolithium reagent into tert-
butyl isocyanide, could be used as viable nucleophiles (Table
1b). Indeed, lithiated aldimines prepared from both commercial
and halogen-derived organolithium reagents (3m – 3r), could be
used to introduce acyl functionality to ketones. Unfortunately,
limitations to the generation of metal aldimines prevented the
incorporation of branched organolithium nucleophiles.
In addition to the wide scope of nucleophiles, the enolate
intermediates generated by conjugate addition were intercepted
with various electrophiles to form α,β-functionalized products
(Table 2). Primary and secondary (cyclic and acyclic)
nucleophiles generated enolates that were efficiently methylated
with methyl iodide in the presence of HMPA to afford products
4a – 4d. The use of other reactive electrophiles such as allyl (4e
– 4g) and benzyl (4h, 4i) halides was also tolerated. The enolate
intermediate could also participate in an aldol addition with
monomeric formaldehyde as an electrophile and ZnCl2 as a
crucial promoter to give the α-hydroxymethyl ketone products 4j
– 4l in high yields. It should be noted that this one-pot α,β-vicinal
difunctionalization process proceeds with diastereoselectivity
consistent with classical half-chair transition state theory.[1]
To demonstrate the synthetic utility of this method, various
precursors to biologically active compounds were prepared more
efficiently than in previous reports. With our telescoped process,
ketones 3aj – 3al, which are intermediates en route to the
bioactive compounds (–)-hibiscone C,[12a] cyclobakuchiol B,[12b]
and 11-Nor-Δ8-THC methyl ester,[12c] were obtained from (+)-
nopinone in a single step with good yield, and compared
favorably to previous preparations as indicated in Figure 3. Our
method could also be utilized for the diastereoselective
Both primary (3s – 3x) and more hindered secondary cyclic
and acyclic alkyl nucleophiles were also efficiently introduced
with predictable diastereoselectivity and provided ketones with
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10.1002/anie.201704874
Angewandte Chemie International Edition
COMMUNICATION
O
Me
Me
H
O
Institutes of Health-funded Chemistry Biology Interface Training
Program (D.H., T32GM067543).
standard
conditions
Me
O
ref. 12a
Me
Me
Me
Me
O
3aj
1a
O
Telescoped: 65%
3 Steps[12a]: 25%
Keywords: palladium • synthetic methodolgy • natural products •
(−)-hibiscone C
(+)-nopinone
vicinal difunctionalization
O
Me
O
[1]
[2]
For a review on α,β-vicinal difunctionalization of enones, see: M. J.
Chapdelaine, M. Hulce in Organic Reactions, Vol. 38 (Eds.: L. A.
Paquette), Wiley, 1990, pp. 225–653.
For reviews on ketone dehydrogenation, see: a) S. S. Stahl, T. Diao,
Comp. Org. Synth. 2014, 7, 178–212; b) J. Muzart, Eur. J. Org. Chem.
2010, 3779–3790; c) A. Turlik, Y. Chen, T. R. Newhouse, Synlett 2016,
27, 331–336.
For a review on step economy in organic synthesis, see: P. A. Wender,
V. A. Verma, T. J. Paxton, T. H. Pillow, Acc. Chem. Res. 2008, 41, 40–
49.
For a recent review on directed metalation by Pd, see: J. He, M. Wasa,
K. S. L. Chan, Q. Shao, J.-Q. Yu, Chem. Rev. 2017, DOI:
10.1021/acs.chemrev.6b00622.
standard
conditions
Me
ref. 12b
Me
Me
Me
3ak
OMe
Me
OH
1a
Telescoped: 82%
3 Steps[12b]: 76%
cyclobakuchiol B
(+)-nopinone
O
[3]
[4]
COOMe
OH
O
OEE
standard
conditions
Me
Me
ref. 12c
Me
Me
Me
EEO
3al
n-C5H9
1a
O
n-C5H9
Me
(+)-nopinone
[5]
[6]
For a review on β-functionalization, see: Z. Huang, G. Dong,
Tetrahedron Lett. 2014, 55, 5869–5889.
Telescoped: 61%
3 Steps[12c]: 30%
11-Nor-Δ8-THC methyl ester
For catalytically formed enamines, see: a) M. T. Pirnot, D. A. Rankic,
D. B. C. Martin, D. W. C. MacMillan, Science 2013, 339, 1593–1596; b)
J. L. Jeffrey, F. R. Petronijević, D. W. C. MacMillan, J. Am. Chem.
Soc. 2015, 137, 8404–8407; c) F. R. Petronijević, M. Nappi, D. W. C.
MacMillan, J. Am. Chem. Soc. 2013, 135, 18323–18326.
For ketone β-functionalization via an intermediate enone, see: a) Z.
Huang, G. Dong, J. Am. Chem. Soc. 2013, 135, 17747–17750; b) Z.
Huang, Q. P. Sam, G. Dong, Chem Sci. 2015, 6, 5491–5498; c) X. Jie,
Y. Shang, X. Zhang, W. Su, J. Am. Chem. Soc. 2016, 138, 5623–5633;
d) X. Hu, X. Yang, X.-J. Dai, C.-J. Li, Adv. Synth. Catal. 2017, 359,
DOI:10.1002/adsc.201700277; e) J. Zhou, G. Wu, M. Zhang, X. Jie, W.
Su, Chem. Eur. J. 2012, 18, 8032–8036; f) Y. Shang, X. Jie, J. Zhou,
P. Hu, S. Huang, W. Su, Angew. Chem. Int. Ed. 2013, 52, 1299–1303.
For ester β-functionalization via an intermediate α,β-unsaturated ester,
see: a) A. Renaudat, L. Jean-Gérard, R. Jazzar, C. E. Kefalidis, E.
Clot, O. Baudoin, Angew. Chem. Int. Ed. 2010, 49, 7261–7265; b) P.
Larini, C. E. Kefalidis, R. Jazzar, A. Renaudat, E. Clot, O. Baudoin,
Chem. Eur. J. 2012, 18, 1932–1944; for β–ketoesters, see: c) M. K.
Leskinen, K.-T. Yip, A. Valkonen, P. M. Pihko, J. Am. Chem. Soc.
2012, 134, 5750–5753.
O
O
H
Me
H
H
Telescoped: 56%
3 Steps[18]: 54%
Telescoped: 59%
6 Steps[19]: 35%
OH
( )10
N
Me
H
[7]
[8]
H
Boc
MeO
3am
3an
Figure 3. Application of Telescoped Process to Multistep Synthesis.
derivatization of a cis-decahydroquinoline ring system in a single
step, affording 3am in 56% isolated yield, thus improving on the
previous report which required three steps.[18] Our one-pot
dehydrogenation – conjugate addition sequence also provided
steroid 3an after tetrahydropyranyl ether (OTHP) cleavage in
59% yield over two steps. The previously reported sequence
accessed 3an in six steps with only a 35% overall yield.[19] By
increasing product yield while also reducing the number of
synthetic steps, we hope this method will find broad utility in
applications related to natural products synthesis and drug
discovery.
In conclusion, we have developed a methodology for ketone
dehydrogenation that finds utility through its efficient telescoping
with foundational organocuprate conjugate addition chemistry.
The broad utility of this protocol arises from an allyl-palladium
catalyzed ketone α,β-dehydrogenation that can be performed on
diverse, unactivated ketone starting materials. The α,β-vicinal
difunctionalization component capitalizes on the well-established
scope and diastereoselectivity of organocuprate conjugate
addition chemistry to introduce a wide selection of functionalities
to ketones. We expect the broad generality of both the individual
transformations and the step economy of the telescoped
process to result in effortless translation to challenges in
multistep synthesis.
[9]
For a review on pot-economy, see: Y. Hayashi, Chem. Sci. 2016, 7,
866–880.
[10]
a) Y. Chen, J. P. Romaire, T. R. Newhouse, J. Am. Chem. Soc. 2015,
137, 5875–5878; b) Y. Chen, A. Turlik, T. R. Newhouse, J. Am. Chem.
Soc. 2016, 138, 1166–1169.
For a review on chiral pool starting materials employed in multistep
synthesis, see: Z. G. Brill, M. L. Condakes, C. P. Ting, T. J. Maimone,
Chem. Rev. 2017, DOI: 10.1021/acs.chemrev.6b00834.
For use of nopinone in synthesis of bioactive compounds, see: a) Y.
Lu, H. Yuan, S. Zhou, T. Luo, Org Lett. 2017, 19, 620–623; b) H.
Kawashima, Y. Kaneko, M. Sakai, Y. Kobayashi, Chem. Eur. J. 2014,
20, 272–278; c) M. A. Tius, G. S. K. Kannangara, J. Org. Chem. 1990,
55, 5711–5714.
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[12]
[13]
J. Grimshaw, J. T. Grimshaw, H. R. Juneja, J. Chem. Soc., Perkin
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[14]
[15]
[16]
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[18]
[19]
Acknowledgements
This work was supported by Yale University, the Sloan
Foundation, and the National Science Foundation (CAREER,
1653793). We are grateful for the support of a Rudolph J.
Anderson postdoctoral fellowship (Y.C.) and the National
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Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Dr.Yifeng Chen, David Huang†, Yizhou
Zhao†, Prof. Dr. Timothy R. Newhouse*
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O
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Page No. – Page No.
E+
+
R
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CuLn
R
Pd(II)Ln
Two for one: Zinc enolates are
employed as intermediates in ketone
dehydrogenation using allyl-palladium
catalysis, which allows for telescoping
with organocuprate conjugate addition
chemistry.
ketone α,β-dehydrogenation
vicinal difunctionalization
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