Ketone Synthesis by Direct, Orthogonal Chemoselective Hydroacylation of Alkenes with Amides: Use of Alkenes as Surrogates of Alkyl Carbanions

Article abstract of DOI:10.1002/cjoc.201900252

Direct functionalization of alkenes and direct transformation of carboxamides are two exciting areas that have attracted considerable attention in recent years. We report herein that secondary amides, the least reactive derivatives of carbonyl compounds, upon activated with triflic anhydride, can serve as effective hydroacylating reagents in partner with alkenes to yield ketones at ambient temperature. The method was applied to the one-step synthesis of racemic dihydro-ar-turmerone. In this method, alkenes serve as surrogates of organometallic reagents, which allows the orthogonal chemoselective reactions. The ready availability of many olefins such as camphene and norbornene permits one-step ketone synthesis that would require several steps by conventional methods.

Full text of DOI:10.1002/cjoc.201900252

Chinese Journal
of Chemistry
CJC
中 国 化 学 - An International Journal
Accepted Article
Title: Ketone Synthesis by Direct, Orthogonal Chemoselective Hydroacylation of
Alkenes with Amides: Use of Alkenes as Surrogates of Alkyl Carbanions
Authors: Hui Geng and Pei-Qiang Huang*
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Ketone Synthesis by Direct, Orthogonal Chemoselective Hydroacylation
of Alkenes with Amides: Use of Alkenes as Surrogates of Alkyl
Carbanions
Hui Geng and Pei-Qiang Huang*
Department of Chemistry, Fujian Provincial Key Laboratory of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University,
Xiamen, Fujian 361005, P. R. China
Cite this paper: Chin. J. Chem. 2019, 37, XXX—XXX. DOI: 10.1002/cjoc.201900XXX
Abstract Direct functionalization of alkenes and direct transformation of carboxamides are two exciting areas that have attracted considerable attention
in recent years. We report herein that secondary amides, the least reactive derivatives of carboxylic acids, upon activated with triflic anhydride, can serve
as effective hydroacylating reagents in partner with alkenes to yield ketones at ambient temperature. The method was applied to the one-step synthesis
of racemic dihydro-ar-turmerone. In this method, alkenes serve as surrogates of organometallic reagents, which allows the orthogonal chemoselective
reactions. The ready availability of many olefins such as camphene and norbornene permits one-step ketone synthesis that would require several steps by
conventional methods.
amides (Scheme 1, b).11
In all the above-mentioned methods, organometallic reagents
Introduction
In organic chemistry, ketone is one of the most versatile
are used as the alkylating reagents. In classical organic chemistry,
functional groups for C–C bond formation. Numerous methods
reactive organometallic reagents such as organolithium and
have been developed for the synthesis of ketones.1 Among them,
Grignard reagents represent the most versatile carbon
the conversion of carboxylic acid derivatives into ketones by
nucleophiles for C–C bond formation. In the context of developing
addition of organometallic reagents occupy a central position.
chemoselective and sustainable transformation, the major
concern in contemporary organic synthesis,12 the use of
However, due to the well-known problem of over addition,
indirect methods consisting of pre-conversion of carboxylic acids
organometallic reagents as alkylating agents presents several
or esters into specially designed carboxylic derivatives such as
drawbacks. For example, organometallic reagents need to be
thioesters2 or chelating amides such as N-methyl-N-methoxy
prepared from a stoichiometric amount of organic halides and a
amides (Weinreb’s amides), 3 followed by organometallic reagents
stoichiometric amount of metals in an anhydrous organic solvent.
addition, are employed routinely for the synthesis of ketones from
Moreover, the inherent high reactivity of organometallic reagents
carboxylic acids and esters (Scheme 1, a). Nevertheless, the
(highly nucleophilic, highly basic, and highly hygroscopic) make
above-mentioned methods cannot be used for the synthesis of
them of low functional group tolerance towards both electrophilic
ketones from common carboxamides (N-monoacylamines), the
and nucleophilic partners.
Olefins are a class of abundant chemical feedstocks. The
least reactive carbonyl compounds. Carboxamides are easily
available4 and bench stable compounds, and amide group is
functionalization of alkenes has attracted considerable attention
in recent years.1a,13 Recently, we have developed mild methods for
widely used as a directing group for both classical metalation –
functionalization5 and modern C–H functionalization.6 Thus, the
transformation of common carboxamides into ketones is in high
demand.
the coupling of alkenes and arenes with N-(2,6-dimethyl)
secondary amides 1A to give a,b-unsaturated enones 4 and
aromatic ketones, respectively (Scheme 1, c). In those reactions,
In recent years, the direct transformations of amides have
alkenes/ arenes serve as mild alternates of alkenyl/aryl carbanions
attracted considerable attention,7 which cumulated in a number of
chemoselective C–C bond forming methods.8 However, the direct
conversion of amides to ketones remains rare. In 2012, the
Charette’s group9 and our group10 reported independently the
chemoselective syntheses of ketones by addition of
organometallic reagents (RMgX/R2Zn;9 RMgX/RLi-CeCl310) to triflic
anhydride (Tf2O)/2-F-Pyr.-activated secondary amides (Scheme 1,
b). In 2015, our group also developed a ketone synthesis by
addition of Grignard reagents to Tf2O/DTBMP-activated tertiary
A.14 During one of those investigations, we discovered that upon
activating with triflic anhydride (Tf2O), secondary amide 1B can
couple with styrene (3A) and allyltrimethylsilane (3B) to yield
saturated ketones 2A and 2B, respectively (Scheme 1, d).10b
Recognizing the importance and challenging of this reaction, a
systematic investigation on this reaction was undertaken.15 Very
recently, Maulide and coworkers have reported
a similar
reaction.16 This prompted us to report our own findings that is
summarized in Scheme 1, e. Our results show that alkenes can be
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Wang et al.
Report
used as surrogates of highly reactive alkyl metallic reagents (alkyl
carbanions B) for the direct transformation of secondary amides 1
into aryl-alkyl ketones and alkyl-alkyl ketones 2.
Scheme 1 Reported methods for ketones synthesis from carboxylic acids and
derivatives and our synthetic plan
H
O
RCO2
O
O
carboxylic acids
Me
O
R
N
R
R1
or
SR'
Results and Discussion
(a)
'
R
R1
R
RCO2
M
Me
esters
thiosters
Mukaiyama
To start our investigation, the coupling of amide 1a with styrene
(3A) was reexamined (Scheme 2). According to our previous
protocol,10b a 0.25 M solution of amide 1B and 2-fluoropyridine
(1.2 equiv) in CH2Cl2 was exposed to Tf2O (1.1 equiv) at 0 °C for 15
min, and the resulted activated intermediated was treated with
styrene (3.0 equiv) at rt for 3 h. After work-up with 2 M HCl, the
desired ketone 2A10b was isolated in 62% yield, along with
a,b-enimine 6a14a,c in 25% yield. Similarly, the reaction of amide
1a produced ketone 2A in 63% yield and a,b-enimine 6b in 25%
yield. For the later reaction, if acidic work-up was performed by
refluxing the reaction mixture in 3 M HCl/ EtOH for 6 h, ketone 2A
and a,b-enone 4A14a,c were obtained in 64% and 24% yield,
respectively. To our delight, the reaction of a-methylstyrene (3a)
with 1a yielded, after work up with an aqueous NH4Cl, ketone 2a
in 85% yield, and only trace of enone 4a was observed.
Weinreb amides
M
solvent
coupling2a
Fukuyama
Liebeskind
2b
R1X
coupling
Kishi2c
O
Tf2 2-F-Pyr.
O
,
O
2
R'
R
.
N
H
R
R1
R1
R1 Zn
2
9
(b)
/
MgX
(Charette)
R1
Li-CeCl
(R'')
-amides
R1
/
sec
tert-amides
1
MgX
3 (Huang)10
R1
tert-amides, Huang)11
MgX (
Huang14
one-pot
Me
R3
O
R3
R2
H
O
Tf
2-F-Pyr.;
2O,
+
(c)
R
R2
R1
R
N
H
R1
HCl
Me
olefins
4
1A
3
one-pot
Huang10b
O
Tf2
O
equiv)
(1.1
O
;
Ph
Ph
2-F-Py
equiv)
(1.2
2A
3A
from
(d)
(66% yield
O
)
Ph
N
H
1B
Nu
equiv);
HCl
(3.0
aq.
TMS
Ph
SiMe3
:
2B
3B
)
from
Nu
Ph
;
(67% yield
(1)
(2)
3A
3B
work:
This
one-pot
Tf2 base
R3
R3
R2
O
H
R'
R'
O
H
O
,
+
+
(e)
R
R2
R
N
R''
R''
O
R1
R1
H
olefins
5
1
2
3
work:
This
Huang14
R3
c
R3
R2
R3
eq
eq
d,e
H
R1
R2
R2
R1
R1
B
A
3
( )
olefins
alkyl carbanions
alkenyl carbanions
Scheme 2 Reinvestigation and preliminary investigation of the couplings of
amides 1B and 1a with styrene
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Chin. J. Chem. 2019, 37, XXX－XXX
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Running title
Chin. J. Chem.
R
derivatives bearing either an electron-donating group (Me, OMe,
entries 2 and 3) or an electron-withdrawing group at para- and
meta-positions (Br, 3,4-diCl, entries 4 and 5). Attenuate yields (67%
and 69%) were obtained from m- and o-bromobenzamides
(entries 6 and 7), which might due to steric hindrance for the latter
case. Remarkably, the reaction demonstrated excellent functional
group tolerance.9 Benzamide derivatives bearing sensitive
substituents: nitro, cyano, ester, acetate, ketone, and even
aldehyde (formyl) groups reacted chemoselectively at the least
reactive secondary amide group to give the corresponding
functionalized ketones 2h - 2m in respectable 61% to 80% yields
(entries 8 - 13). Similar chemoselectivity was observed for
benzamides bearing a p-phenyldiazenyl and acetal groups (entries
14 and 15). Tertiary and secondary amide groups can also be
distinguished with the latter being more reactive (entry 16). Good
yields were obtained from N-isopropyl-2-naphthamide (1q) and
electron-rich N-isopropylbenzo[b]thiophene-2-carboxamide (1r)
(entries 17 and 18).
O
M)
HCl
r.t.
N
aq.
(2
+
+
Ph
Ph
Ph
6a
Ph
Tf2
2-F-Pyr.
O
equiv)
c
(1.1
=
2A
2A
R
-hexyl
=
i-Pr
(62%)
(63%)
O
(25%)
(25%)
equiv)
(1.2
R
6b
R
Ph
(R
N
M)
CH2Cl
0 ºC, 15 min;
H
2 (0.25
N)
HCl
aq.
(3
EtOH
O
O
1B
c
=
3A
Ph
(
-hexyl)
)
Ph
Ph
+
Ph
4A
Ph
reflux, 6 h
1a
equiv
(3.0
)
=
R
i-Pr
=
2A
i-Pr)
(64%)
Ph
(R
(24%)
O
Tf
2-F-Pyr.
O
O
2O,
i-Pr
Ph
Ph
Ph
Ph
N
H
4a
trace
2a
85%
3a
3.0
,
equiv)
Ph
(
1a
r.t., h;
0 ºC to
aq.
3
NH
4Cl
Next, we selected N-i-propylbenzamide (1a) as a prototype
amide substrate, and a-methylstyrene (3a), a bulk chemical used
in the polymer industry, as a nucleophile for our investigation. In
view of the successful use of Tf2O as a powerful amide activating
agent in our previous investigations, we opted for this easily
available reagent for amide activation, and the effect of base
partner was first examined. It was encouraging to observe that
treating a mixture of amide 1a and Tf2O with a-methylstyrene (3a)
resulted in the clean formation of the desired ketone 2a in 30%
yield, along with the recovered starting amide in 59% yield (Table
1, entry 1). Whereas yield of 2a was slightly improved with the use
of triethylamine, pyridine is detrimental for the reaction.
Encouragingly, good yields of 2a were obtained by employing
pyridine derivatives such as 2-chloropyridine (2-Cl-Pyr.),
2-fluoropyridine (2-F-Pyr.), 2,6-di-tert-butylpyridine (DTBP), and
2,6-di-tert-butyl-4-methylpyridine (DTBMP), and 2-F-Pyr. turned
out to be the most efficient base partner examined, affording the
desired ketone 2a in 88% yield (determined by NMR, 85% isolated
yield). A survey of amount of nucleophile 3a showed that 1.2 equiv.
to be optimal, which produced ketone 2a in 88% NMR yield (85%
isolated yield) (see Table S1 in supporting information).
The reaction could be extended to both a,b–unsaturated
(entry 19) and aliphatic amides (entries 20 and 21). Moreover,
secondary amides bearing other N-substituents such as primary
benzyl and allyl groups (entries 23 and 24) could be used as viable
substrates. Interestingly, the reaction of amide bearing
a
secondary alkyl group 1y yield, besides the desired ketone 2a in 78%
yield, another ketone 7a in 65% yield (entry 25). The isolation of
4-phenylbutan-2-one (7a) is significant for understanding the
mechanism of the reaction (vide infra).
Table 2. Amide scopea
Table 1. Screening of base.
Tf2
CH2Cl
Base
O
equiv),
equiv)
min
(1.1
(1.2
0 ºC, 15
O
O
2 (0.25 M),
i-Pr
Ph
N
Ph
Ph
H
base
equiv)
(1.2
0 ºC to r.t., 3 h
then
NH Cl
2a
1a
Ph
equiv)
aq.
3a
4
(1.2
Entry
Base (1.2 equiv)
2a (% yield)a
1a (% yield)a
1
2
3
4
5
6
7
None
Et3N
Pyr.
2-Cl-Pyr.
2-F-Pyr.
DTBP
30
45
10
60
59
15
75
trace
trace
trace
trace
88 (85)b
75
82
DTBMP
With the optimal reaction conditions in hand, the scope of
amide substrate was surveyed, and the results are summarized in
Table 2. The substituent effect on the phenyl ring was first
examined. The reaction worked smoothly with benzamide
Chin. J. Chem. 2019, 37, XXX－XXX
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Wang et al.
Report
products were not determined, in light of our recent results,17
exo-substituted diastereomers were assume.
one-pot
2-F-Pyr.
Tf O
(1.1 equiv),
CH2Cl
(1.2 equiv)
0 ºC, 15 min
2
O
O
The advantages of using neutral alkenes as surrogates of
reactive organometallic reagents (alkyl carbanions) is multiple. On
one hand, not only it allows the use of amides bearing sensitive
functional groups (e.g. 1h - 1p), but also it permits employing
functionalized alkenes. The latter feature is showcased by alkenes
3m – 3p bearing OTBS, OAc, and chloro substituents. On the other
hand, the ready availability of many olefins such as commercially
available terpenes camphene (3k) and norbornene (3l), as
compared with the corresponding carbanions or organohalides
represents another singular feature of the method. Interestingly,
depending on the work-up conditions, phenol acetate in 3p could
either survival from the reaction or cleaved concomitantly to
deliver directly free phenol group. Such features are not possible
for the traditional addition reactions employing RM as
nucleophiles.
2 (0.25 M),
R2
R1
N
H
R1
Ph
0 ºC to r.t., 3 h
2
1
Ph
(a-v)
(a-y)
3a
O
1.
2.
3.
4.
5.
6.
R3
14.
=
=
1a
2a
,
H;
(85%)
i-Pr
R3 p-Me,
R3 p-OMe,
R3 p-Br,
1b
2b
,
(82%)
N
b
H
=
1c
2c
,
(81% )
N
Ph
N
=
1d
2d
,
(82%)
2e
R3
R3
=
1e
,
3,4-diCl,
-Br,
(81%)
(67%)
2g (69%)
n
1n
2
;
O
(82%)
O
m
=
1f
2f
,
i-Pr
7. 1g R3
-Br,
-
N
H
o
15.
=
,
R3
R3 p NO2
=
1h
2h
8.
9.
,
,
i-Pr
(74%)
(75%)
O
N
H
R3 p-CN,
R3 p-CO Me,
R3 p-OAc,
R3 p-COMe,
=
1i
2i
,
O
=
1j
10.
11.
12.
13.
,
2j
2k
(80%)
(75%)
2l
2
=
1k
,
b
1o; 2o
(75% )
=
1l
,
(70%)
2m
R3 p-CHO,
=
1m
,
(61%)
Table 3. Alkene scope
O
O
16.
Et
O
17.
18.
one-pot
i-Pr
i-Pr
i-Pr
N
N
H
Tf2
2-F-Pyr.
O
N
H
(1.1 equiv),
CH2Cl
(1.2 equiv)
0 ºC, 15 min
H
O
N
R3
S
2 (0.25 M),
O
Et
i-Pr
Ph
N
R3
O
R2
H
H
Ph
r.t.,
0 ºC to
3
h
1r; 2r
1q; 2q
(85%)
O
(86%)
1p; 2p
(70%)
O
H
R1
1a
R1
3
R2
(a-p)
-
2
2al)
(w
19.
20.
21.
O
i-Pr
i-Pr
a
N
H
a
i-Pr
2
Product
N
2
(yield)
Alkene
Product
O
Alkene
(yield)
N
H
H
O
1s; 2s
(80%)
1u; 2u
1t; 2t
(77%)
(77%)
Bn
Ph
Ph
2ae
3j
23.
22.
25.
24.
X
(70%)
O
O
X
O
=
=
Me
=
=
=
=
=
=
c
3a
3b
3c
3d
2a
2w
2x
2y
H
85%)
,
H)
Me)
OMe)
Cl)
-Hex
(X
(X
(X
(X
(X
N
H
N
N
H
X
90%)
,
O
(
H
X
X
OMe
,
92%)
(
(
Ph
Cl
82%)
,
1x; 2a
1v; 2v
1w; 2a
(82%)
(78%)
(75%)
Ph
O
2af
(83%)
O
O
3k
3l
O
+
Ph
O
Ph
N
H
1y
Ph
Ph
Ph
2z
(82%)
Ph
2a
7a
(78%)
(65%)
3e
O
°
run
at 40 C.
a Isolated
b The
step
2ag
(91%)
yield;
coupling
S
S
Ph
O
We next examined the scope of alkene (Table 3). Excellent yields
were obtained from a-methylstyrenes bearing an
electron-donating group (3b: Me, 90%; 3c: OMe, 92%) at
para-position of the prop-1-en-yl group, and an 82% yield was
b
Ph
X
+
2aa
10%
3f
Ph
(70%
)
X
Ph
O
=
=
3m X
3n X
OTBS
OAc
2ah
2ai
(72%)
(70%)
Ph
Ph
Ph
obtained
from
a-methyl-(p-chlorostyrene)(3d).
Other
3g
Ph
Ph
O
2ab
(72%)
Ph
prop-1-en-2-ylarenes such as 2-(prop-1-en-2-yl)naphthalene (3e)
and 2-(prop-1-en-2-yl)thiophene (3f) reacted with similarly
efficiency, but 10% of the eliminated side product (4a) was also
yielded from 3f. The yield (72%) from the reaction of
ethene-1,1-diyldibenzene (3g) is lower than expected, whereas
that (71%) from cyclopropylvinyl derivative (4h) is higher than
Cl
Cl
3
Ph
Ph
O
3o
2aj
(65%)
Ph
O
2ac
(71%)
3h
Ph
O
OAc
Ph
OAc
OH
2ak
3p
3p
expected considering
a possible rearrangement. Apart from
(61%)
2ad1
prop-1-en-2-ylarenes, alkenes can be extended to non-styrene
derivatives such as 2,2-disubstituted terminal alkenes (3i and 3j).
Significantly, naturally occurring and commercially available
80%
15)
aq.
O
(85:
O
3i
Ph
Ph
OAc
c
terpenes camphene (3k) and norbornene (3l),
a special
2ad2
2al
(60% )
1,2-dialkylalkene, served as excellent alkene partners furnishing
the corresponding ketones in excellent yields (2af: 83%; 2ag: 91%)
as single diastereomer. Although the stereochemistries of the
,
a Isolated
Work-up with sat.
a
NH Cl; b Yield of
4
-enone
4b
;
b
yield,
c Work-up with 3 M HCl/ EtOH.
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Running title
Chin. J. Chem.
A plausible mechanism for the hydroacylation reaction is
depicted in Scheme 5. Central to the mechanism is the generation
of a highly reactive nitrilium intermediate B upon treatment of a
secondary amide with Tf2O, which has been detected in our
previous work by both in situ IR and 2D NMR techniques.14a,19
Another key point resides in the 1,5-hydride transfer that has been
suggested when this reaction was discovered for the first time.10b
The easy release of a ketone from the reaction just by work up
Because secondary amides are products of many synthetic
methodologies,4 the transformation of such products were
envisioned (Scheme 3). In 2014, Fu reported a mild method for the
synthesis of secondary amides featuring photoinduced,
copper-catalyzed alkylation of amides with unactivated secondary
alkyl halides at room temperature.4a The coupling of one of its
product
1z with a-methylstyrene (3a) yielded ketone 2v in 70% yield, along
with ketone 7a in 35% yield. The hydroacylation of
a-methylstyrene (3a) with amide 1aa, a Beak’s secondary amide
directed methylation product,5b afforded ketone 2am in 81% yield.
The reaction of a-methylstyrene (3a) with o-iodobenzamide 1ab, a
secondary amide-directed C–H functionalization product
described by Glorius,6d afforded ketone 2an in 44% yield, along
with enamine 6c in 46% yield.
with a sat. aqueous NH4Cl is in support of the reactive
intermediate D. The observation of the formation of 6 and 7 in
some cases provides supports for the suggested mechanism.
Moreover, the formation of enimine 6c (Scheme 3) as the major
product can be understood in terms of an intramolecular I⋅⋅⋅⋅H
interaction (cf. G in Scheme 5), which favors the b-elimination, and
yields 6c as the major product.
(+)-(S)-ar-turmerone (8) and (+)-(S)-dihydro-ar-turmerone (9)
Scheme 4. One-step synthesis of racemic dihydro-ar-turmerone
belong
to
bisabolane-type
sesquiterpenoids.18
These
O
Tf O
CH2Cl
2-F-Pyr
(1.1 equiv),
(1.2 equiv)
0 ºC, 15 min
2
O
2 (0.25 M),
sesquiterpenoids possess a variety of biological activities including
acetylcholinesterase inhibitory activity.18b To further demonstrate
the synthetic potential of our method, the synthesis of
dihydro-ar-turmerone (9) was undertaken. Simply by subjecting
amide 1ac to the standard hydroacylation with a-methylstyrene
derivative (3b), the desired racemic dihydro-ar-turmerone (9) was
synthesized in 73% yield.
i-Pr
N
H
9
ar
25 ºC, 3 h
73%
1ac
-turmerone
dihydro-
3b
O
O
9
S
8
(+)-( )-
ar-
turmerone
ar
-turmerone
S
Scheme 3. The transformation of amides available by modern synthetic
S
(+)-( )-
(+)-( )-dihydro-
methodologies
O
O
Me
O
Tf
2-F-Pyr.
2O,
Me
Ph
Ph
N
H
Ph
7a
35%
+
2v
1z
Ph
70%
3a
O
O
Tf
2-F-Pyr.
2O,
i-Pr
N
H
2am
(81%)
I
Ph
3a
1aa
I
O
Ni-Pr
I
O
Tf
2-F-Pyr.
2O,
i-Pr
Ph
+
Ph
N
H
1ab
Ph
2an
6c
(44%)
(46%)
3a
Scheme 5. Plausible mechanism of the reaction
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
This article is protected by copyright. All rights reserved.

Tf-O-Tf
Ph
R1
Ph
R1
O
Ph
Ph
B:
TfO
R1
R
H
R
H
H
R
R
Ph
N
H
R2
d
Ph
H
R1
1
N
a
Ph
N
Ph
N
R2
R2
R2
TfO
6
Tf
2O
C
B
2- F-Pyr
R1
c
OTf
Ph
Ph
N
Ph
N
H
R2
R
R
Ph
H
2-
F
N
F-Pyr-HOTf
Ph
H
TfO
N
R1
aza-ene
A
N
H
Ph
Ph
R1
TfO
b
TfO
R2
R2
Ph
B
D'
D
TfO
R
H
I
H
H
3O
R1
Ph
Ph
N
Ph
R2
R
R1
R
O
OH
N
R
OH
R1
G
+
+
Ph
R1
R2
Ph
TfO
N
H
=
aryl
R
Ph
O
H,
alkyl,
NH
4OTf
H
R2
7
R2
TfO
2
E
F
Conclusions
Tf2O (185 μL, 1.1 mmol, 1.1 equiv) was added dropwise to a
cooled (0 °C) solution of a secondary amide (1.0 mmol, 1.0 equiv)
and 2-fluoropyridine (103 μL, 1.2 mmol, 1.2 equiv) in
dichloromethane (4 mL, 0.25 M). The reaction was stirred for 15
min at 0 °C. To the resulting mixture, an alkene (1.2 mmol, 1.2
equiv) was added dropwise at 0 °C. The mixture was allowed to
warm-up to room temperature (or 40 °C) and stirred for 3 h. The
reaction was quenched with a saturated aqueous NH4Cl solution
(3 mL), and the mixture was extracted with CH2Cl2 (3 × 10 mL). The
combined organic layers were washed with a saturated aqueous
solution of sodium carbonate (5 mL) and brine (5 mL), dried over
anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by column chromatography on
silica gel eluting with ether/petroleum ether to afford the desired
ketone.
Starting from our recent finding, we have established an
expedient and sustainable method for the synthesis of ketones
from alkenes and amides. Running at room temperature, and
employing neutral alkenes to replace conventionally used highly
basic organometallic reagents as nucleophiles, the reactions
conditions are quite mild. As a result, several sensitive functional
groups on either nucleophilic partner (alkenes) or nucleophilic
partner (amides) are tolerated. Moreover, the use of abundant
and stable chemical feedstocks such as bulk chemicals
a-methylstyrene, naturally occurring camphene and norbornene,
permits one-step ketone synthesis that would require several
steps by conventional methods. A detailed mechanism featuring a
1,5-hydride transfer is suggested, which is supported by the
isolation of several side-products. Further exploration of this
method is ongoing in our laboratories, and the results will be
reported in due course.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
Experimental
General procedure for the direct hydroacylation of alkenes
with secondary amides to give ketones.
Acknowledgement
The authors are grateful for the financial support provided by
the National Key R&D Program of China (2017YFA0207302) and
the National Natural Science Foundation of China (21672176 and
21332007). They thank Ms. Yan-Jiao Gao for technical assistance.
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© 2018 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
This article is protected by copyright. All rights reserved.

Running title
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www.cjc.wiley-vch.de
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(The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2019
Manuscript revised: XXXX, 2019
Manuscript accepted: XXXX, 2019
Accepted manuscript online: XXXX, 2019
Version of record online: XXXX, 2019
www.cjc.wiley-vch.de
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
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Entry for the Table of Contents
Page No. 7
one-pot
Ketone Synthesis by Direct, Orthogonal
Chemoselective Hydroacylation of Alkenes with
Amides: Use of Alkenes as Surrogates of Alkyl
Carbanions
R4
R3
Tf2
O
O
equiv)
H
(1.1
2-F-Pyr.
R4
O
R1
equiv)
(1.2
+
R
N
R2
R
R3
H
rt,
CH2Cl2
3
h
,
amides
R2
common
alkenes
cheap feedstock
cheap feedstock
46
examples;
to 92%
up
yield
=
R
hetero-aryl,
alkenyl,
styryl
aryl,
alkyl, cycloalkyl,
Bn,
allyl, cyclohexyl.
R1 2 º
=
alkyl,
We report the Tf2O-mediated hydroacylation of alkenes with secondary amides, which constitutes
a mild and versatile method for ketone synthesis. The use of cheap feedstock alkenes as surrogates
of organometallic reagents for selective addition to secondary amides, the least reactive carboxylic
acid derivatives, presents several advantages.
Hui Geng and Pei-Qiang Huang*
a Department, Institution, Address 1
E-mail:
c Department, Institution, Address 3
E-mail:
b Department, Institution, Address 2
E-mail:
Chin. J. Chem. 2018, template
© 2018 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
This article is protected by copyright. All rights reserved.