Copper-catalyzed cascade annulation of unsaturated α-bromocarbonyls with enynals: A facile access to ketones from aldehydes

Article abstract of DOI:10.1039/c5sc04980f

A Cu-catalyzed cascade annulation of enynals with alkenyl or alkynyl α-bromocarbonyls for the synthesis of various cyclohexenone-fused polycyclic compounds is described. Up to six new C-C bonds and four new carbocycles can be established in a single reaction, highlighting the high efficiency and step-economics of this protocol. This reaction offers a novel and straightforward entry to the synthesis of ketones featuring the addition of carbon radicals to aldehydes.

Full text of DOI:10.1039/c5sc04980f

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DOI: 10.1039/C5SC04980F
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ARTICLE
Copper-catalyzed cascade annulation of unsaturated α-
bromocarbonyls with enynals: a facile access to ketones from
aldehydes
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
a
a
Chao Che, Qianwen Huang, Hanliang Zheng and Gangguo Zhu *
DOI: 10.1039/x0xx00000x
www.rsc.org/
A Cu-catalyzed cascade annulation of enynals with alkenyl or alkynyl α-bromocarbonyls for the synthesis of various
cyclohexenone-fused polycyclic compounds is described. Up to six new C-C bonds and four new carbocycles can be
established in a single reaction, highlighting the high efficiency and step-economics of this protocol. This reaction offers a
novel and straightforward entry to the synthesis of ketones featuring the addition of carbon radicals to aldehydes.
Ketones are ubiquitous chemical entities in bioactive
1
molecules, drugs, and materials (Scheme 1). Typically, they
are prepared by the addition of organometallic compounds to
aldehydes, followed by oxidation, which requires the
utilization of stoichiometric organometallic reagents and
oxidants.
functionalization
Alternatively,
the
aldehydic
C-H
bond
2
-7
has become a powerful strategy for
assembling ketones because of its outstanding advantages in
atom and step efficiency. Among these, the radical reactions
4
-7
have attracted more and more attention. For example, a N-
hydroxyphthalimide catalyzed radical hydroacylation of simple
4
alkenes with aldehydes has been achieved by the Ishii group.
More recently, Lei and co-workers reported an elegant
synthesis of α,β-unsaturated ketones via the Cu-catalyzed
oxidative coupling of terminal alkenes with aldehydes. It
5
Scheme 1 Examples of bioactive ketones.
should be noted that, most of these reactions depend on the
(
a) type I (donor for carbon radical)
generation and transformation of acyl radical
A
(type I)
7
(
Scheme 2a). However, the type II version, with aldehydes as
O
O
O
O
8
R
R
acceptors for the addition of carbon radicals, has never been
realized for the access of ketones (type II) (Scheme 2b). This
may be ascribed to the higher dissociation energy of C-H bonds
as compared to that of C-C bonds, and consequently, the
R1
R1
R1
R2
H
A
(
b) type II (acceptor for carbon radical)
O
R2
O
C-C -scission
C-H -scission
alkoxyl radical
scission, instead of the C-H β-scission. As such, the
intermediate is in favor of transforming back to aldehydes.
B
strongly prefers to proceed via the C-C β-
R1
R1
R1
R2
H
R2
H
9
B
BH+
CuII
our proposal
B
1
,2-HAT
CuI
Given the high efficiency of this transformation (type II), we
decided to explore the feasibility. While pursuing our recent
work on the Cu-catalyzed atom-transfer radical addition (ATRA)
B
R2 OH
CuII CuI
B = base
R2 OH
2
R X
R1
R1
1
0-12
C
D
of alkynes,
we envisaged that the direct conversion of
Scheme 2 Radical approaches to ketones from aldehydes and our proposal.
aldehydes into ketones might be accomplished via a Cu-
catalyzed redox-neutral pathway, which consists of the
following steps: (1) a single electron transfer (SET) between
2
the Cu(I) catalyst and organohalides (R X) produces a radical
a.
Department of Chemistry, Zhejiang Normal University, 688 Yingbin Road, Jinhua
2
R ·, together with the formation of Cu(II), (2) the alkoxyl radical
B, resulted from the addition of R · to R CHO, undergoes a
formal 1,2-H atom shift to afford the carbon-centered radical
3
21004, China. E-mail: gangguo@zjnu.cn
2
1
Electronic Supplementary Information (ESI) available: Data for all the products,
experimental procedures, CCDC 1439849, 1439850, and 1439851. See
DOI: 10.1039/x0xx00000x
13
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C
, (3) another SET between
cationic intermediate
accompanied by the regeneration of L4 and L5 resulted in decreased yields (eDnOtIr:i1e0s.160-399)/.CR5SeCp0l4a9c8in0gF
the Cu(I) catalyst, and (4) deprotonation of gives ketones as DEAD with either azodiisobutyrodinitrile (AIBN) or 2,2'-azobis-
C and Cu(II) species delivers a in 86% yield (entry 4). Employment of other ligandVsiewsuAcrthicleaOsnLli2ne-
D
D
the final products. Herein, we describe a Cu-catalyzed cascade (2,4-dimethylvaleronitrile) (V65) led to inferior results (entries
annulation of alkenyl or alkynyl α-bromocarbonyls with 10 and 11). As for the solvent, MeCN demonstrated better
enynals, providing a variety of polycyclic ketones in moderate performance than other solvents like THF, toluene, and DMF
to excellent yields under mild reaction conditions. In this (entries 14-16).
reaction, up to six new C-C bonds and four new rings can be
assembled from the readily attained starting materials,
highlighting the high efficiency and step-economics of this
method.
a
Table 2 Scope of enynals
a
Table 1 Optimization of the reaction conditions
Entry
[Cu]
Ligand
L1
L1
L1
L1
L1
L2
L3
L4
L5
L1
L1
L1
L1
L1
L1
L1
Additive
/
Base
Solvent
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
THF
Yield (%)
42
1
2
3
4
5
6
7
8
9
CuBr
CuBr
K
K
K
K
K
K
K
K
K
K
K
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
2
DEAD
DEAD
DEAD
/
36
Cu(acac)
2
83
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
2
86
2
61
2
2
2
2
2
2
2
2
2
2
2
DEAD
DEAD
DEAD
DEAD
AIBN
V65
52
2
2
2
2
2
3
3
3
3
3
34
75
80
1
1
1
1
1
1
0
1
2
3
4
5
6
62
65
DEAD
DEAD
DEAD
DEAD
DEAD
Cs
2
CO
3
47
DBU
21
K
2
K
2
K
2
CO
CO
CO
3
3
3
trace
trace
14
PhMe
DMF
1
a
Reaction conditions: 1a (0.25 mmol), 2a (0.30 mmol), [Cu] (10 mol %), ligand (20
o
mol %), additive (20 mol %), base (0.25 mmol), solvent (3 mL), under N2, 80 C, 10
h. Yields of the isolated products are given.
a
Reaction conditions: 1 (0.25 mmol), 2a (0.30 mmol), Cu(OAc)2 (10 mol %), L1 (20
o
To test this hypothesis, the reaction between 2- mol %), DEAD (20 mol %), K2CO3 (0.25 mmol), MeCN (3 mL), under N2, 80 C, 10 h.
Yields of the isolated products are given. NPhth = phthalimidyl.
ethynylbenzaldehyde
(1a
)
and
diethyl
α-allyl-α-
bromomalonate (2a) was conducted in MeCN. Using 10 mol %
of CuBr as the catalyst, 20 mol of
pentamethyldiethylenetriamine (L1) as the ligand, and 1
equivalent of K CO as the base, tricyclic ketone 3aa was
isolated in 42% yield, after being heated at 80 C for 10 h
Table 1, entry 1). Encouraged by this result, we further
screened the reaction parameters. To our satisfaction, using
diethylazodicarboxylate (DEAD) as the reducing reagent for in
situ generation of the Cu(I) catalyst, the reaction afforded 3aa
With the optimized reaction conditions in hand, we
investigated the scope of this Cu-catalyzed domino annulation
%
by varying enynals
1 and α-bromocarbonyls 2. As shown in
2
3
o
Table 2, the standard conditions were well compatible with a
variety of enynals, including 2-ethynylbenzaldehydes and pent-
(
2
-en-4-ynal derivatives. Substrates with different substituents
on the aryl ring of were successfully converted into polycyclic
ketones in good to excellent yields, regardless of the electronic
effects of the substituents (3ba 3ia). Halogen atoms such as F
1
-
2
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and Cl were well tolerated under the reaction conditions (3da
-
View Article Online
DOI: 10.1039/C5SC04980F
3
fa), giving ample opportunities for further elaboration by the
transition-metal-catalyzed coupling reactions. Intriguingly, the
reaction of 1m-1o with 2a occurred uneventfully to provide
tetracyclic ketones 3ma-3oa in high yields. Aldehyde 1p with
2-thienyl group was transformed into the corresponding
Scheme 3 Cu-catalyzed double cascade annulation.
ketone 3pa in 68% yield. The process was extended to
substrate 1q, bearing an amide group, providing 3qa in a good
By varying α-bromo γ,δ-unsaturated carbonyl compounds
with 1a as the coupling partner, more examples of tricyclic
ketones (3ab 3ai) were synthesized (Table 3). The product 3ab
containing a gem-dimethyl subunit, was isolated in an
excellent yield. Substitution of the terminal C-C double bond of
2
yield. Moreover, 2-ethynylcyclohex-1-enecarbaldehyde (1r
)
was also a competent substrate, and 3ra was synthesized
without erosion of the reaction yield.
-
,
a
Table 3 Scope of α-bromocarbonyl compounds
2
with a methyl group resulted in the production of 3ac in 80%
yield and good diastereoselectivity (dr = 88:12). In contrast,
the Ph-substituted analogue 2d was not suitable for this Cu-
catalyzed domino process (3ad). In the case of β-branched
substrate 2f, the reaction produced 3af in a moderate yield.
The reaction covered other activated organobromides, as
R1
Cu(OAc)2 (10 mol%)
PMDETA (20 mol%)
DEAD (20 mol%)
O
R3 CO2R2
n
3
CHO
R
+
R1
CO2R2
MeCN, 80 o
Br
n
C
n = 1,2
1a
2
3
exemplified by the construction of 3ag and 3ah. Compound 2i
a weakly activated substrate, was effective for the
,
EtO2C CO2Et
Br
EtO2C CO2Et
Br
Br CO2Et
EtO2C CO2Et
R
CO2Et
Br
2b
R = Me (2c), Ph (2d)
2e
2f
transformation, while no detectable product was observed
when secondary bromide 2j was used as the coupling partner
Ac Ac
R
CO Et
R
EtO C CO Et
EtO C CO Et
2
2
2
2
2
(3ai and 3aj). This reaction was well amenable to propargyl α-
Br
Br
Br
R = Me (2k), n-Bu (2l), CH OMe
Me (2i), H (2j) (2m), cyclopropyl (2n), t-Bu (2o)
Br
2g
R = Ac (2h),
2p
bromocarbonyls. For example, the coupling of 1a with 2k took
place as well, affording 3ak in 74% yield. Substitution of the
terminal alkynyl carbon by primary alkyl groups led to the
2
Ph
O
O
O
facile generation of tricyclic ketones (3ak-3am), whereas the
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
cyclopropane-substituted counterpart 2n delivered the
corresponding product in a lower yield (3an), potentially due
to the increased steric hindrance. Meanwhile, α-bromo δ,ε-
unsaturated carbonyl such as 2p performed well in this Cu-
catalyzed cascade annulation reaction, giving a direct and
convenient access to the 6-6-6 tricyclic ketone 3ap. The
structure of polycyclic ketones 3fa and 3ap was determined by
3ab, 92%
3ac, 80% (dr = 88:12)
3ad, trace
3ag, 76%
O
O
O
O
O
CO2Et
CO2Et
CO2Et
CO2Et
Ac
Ac
1
4
3ae, trace
3af, 39% (dr = 61:39)
the X-ray diffraction analysis.
O
Remarkably, the one-pot construction of pentacyclic
diketones 3sa and 3sp was achieved by reacting enynal 1s with
CO2Et
Ac
CO2Et
CO2Et
H
2a and 2p, respectively (Scheme 3). Although the yield appears
to be moderate, considering the formation of six new C-C
bonds and four new rings in a single reaction, it still represents
a highly attractive method for the synthesis of polycyclic
ketones from readily accessible starting materials.
3
ah, 78% (dr = 55:45)
3ai, 80% (dr = 60:40)
n-Bu
3aj, trace
CH2OMe
O
O
O
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
To gain insights into the reaction mechanism, a series of
experiments were performed. Firstly, the reaction between 1a
and 2a was inhibited by adding 2 equivalents of 2,2,6,6-
tetramethylpiperidinooxy (TEMPO), and instead, 4a was
formed in 51% yield (eq 1). In the presence of butylated
hydroxytoluene (BHT), no detectable 3aa was observed, and
3
ak, 74%
3al, 70%
t-Bu
3am, 53%
O
O
O
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
3ap, 81%
Reaction conditions: 1a (0.25 mmol), 2 (0.30 mmol), Cu(OAc)2 (10 mol %), L1 (20
4
b
was obtained in 35% yield (eq 2). Likewise, the addition of
3an, 35%
3ao, trace
1,1-diphenylethylene hindered the reaction between 1a and
a
2b and provided the Cu-catalyzed atom-transfer radical
o
12a
mol %), DEAD (20 mol %), K2CO3 (0.25 mmol), MeCN (3 mL), under N2, 80 C, 10 h. cyclization product 4c in 68% yield (eq 3). These results
Yields of the isolated products are given.
indicated that the Cu-catalyzed cascade annulation reaction
might proceed via a radical mechanism. Furthermore, when
compound
5 was employed as the starting material, alcohol 6a
was obtained in 62% yield (eq 4), implying that the aldehydic
hydrogen atom of
1
is essential for the ketone synthesis.
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Alcohol 6b, generated by the reduction of 3aa with NaBH
subjected to the optimized reaction conditions, and as a result, (Scheme 5). Treatment of 3aa with LiCl and H O in DMSO at
2
no formation of 3aa was observed (eq 5). It indicated that the reflux resulted in the production of 80% yield of 3aj, a
formation of alcohol intermdiate 6b followed by oxidation with product that was not able to be synthesized via the Cu-
Journal Name
4
, was
The synthetic utility of this reaction was also explored
View Article Online
DOI: 10.1039/C5SC04980F
1
5
Cu(II) reagents is less likely in this case.
catalyzed cascade annulation (Table 3, 3aj). Obviously, the
decarbalkoxylation procedure offered a good complementary
method to the domino annulation. Epoxidation of 3fa with
meta-chloroperbenzoic acid (m-CPBA) gave rise to a single
1
4
diastereoisomer, 7b, in 76% yield. Furthermore, the one-pot
synthesis of α-bromo diketone 7c could be accomplished
through the exposure of 3aa to a combination of N-
1
6
bromosuccinimide (NBS) and NH
4 2
OAc in Et O. By treating 3ak
with NaBH in a 1:1 mixture of MeOH and THF, the 1,6-
4
addition product 7d was obtained in 92% yield, which
constitutes a new efficient access to polysubstituted 1-
1
7
naphthols.
O
O
CO2Et
CO2Et
CO2Et
H
LiCl, H2O
DMSO, reflux
3aa
3aj, 80% (dr = 54: 46)
H
O
O
CO2Et
CO2Et
CO2Et
CO2Et
m-CPBA
CH2Cl2, rt
O
H
R
R
R = H, 3aa
R = Cl, 3fa
R = H, 7a, 82%
R = Cl, 7b, 76%
O
Br
O
O
CO2Et
CO2Et
CO2Et
NBS, NH4OAc
Et2O, rt
CO2Et
3
aa
7c, 76%
7d, 92%
O
HO
CO2Et
NaBH4
CO2Et
CO2Et
CO2Et MeOH/THF, rt
3
ak
Scheme 5 Synthetic utility of cascade annulation.
Scheme 4 A possible mechanism.
Conclusions
Whereas the full mechanistic features of this Cu-catalyzed
domino annulation are still under investigation, a working
mechanism is proposed in Scheme 4, using 1a and 2a as
We have developed a Cu-catalyzed cascade annulation of
enynals with alkenyl or alkynyl α-bromocarbonyls, yielding
various cyclohexenone-fused polycyclic compounds under mild
reaction conditions. Up to six new C-C bonds and four new
rings can be established in a single reaction, highlighting the
high efficiency of this protocol. A wide range of functional
representative starting materials. Initially, a radical
by a SET process from 2a and Cu(I) catalyst, which is generated
in situ by the reduction of Cu(OAc) with DEAD. The isolation of
adduct 4a confirmed the formation of radical
adds to the C-C triple bond of 1a to deliver an alkenyl radical II
I is formed
2
I
. The radical
I
3 2
groups such as F, Cl, OMe, CF , CO Et, Ac, amide, thienyl, and
,
alkyl substituents are well tolerated. This reaction represents a
novel method for the one-step synthesis of ketones featuring
the addition of carbon radicals to aldehydes. Further
investigations on the reaction mechanism and application to
bioactive ketones are currently undergoing in our laboratory.
which is converted to the alkyl radical species III via a 5-exo-
trig cyclization. Then, an intramolecular addition of carbon
radical to the aldehyde group generates the alkoxy radical IV
,
1
3
followed by a formal 1,2-H shift to give the benzyl radical
Subsequently, a second SET between
V.
V
and Cu(II) produces the
cationic intermediate VI with the regeneration of Cu(I) catalyst.
Finally, VI is deprotonated to afford the tricyclic ketone 3aa
with the aid of K CO .
2 3
Acknowledgements
4
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Province (2015C31030), Natural Science Foundation of
Zhejiang Province (LR12B02001), and National Natural Science
Foundation of China (21172199) for the financial support.
(
2
DOI: 10.1039/C5SC04980F
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For selected reviews on ketone synthesis via hydroacylation,
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