Halogen-Substituted Allenyl Ketones through Ring Opening of Nonstrained Cycloalkanols

Article abstract of DOI:10.1021/acs.orglett.1c00452

An efficient synthesis of halogen-substituted allenyl ketones via Ag-catalyzed oxidative ring opening of allenyl cyclic alcohols under mild reaction conditions has been achieved. The reaction features a wide substrate scope and excellent regioselectivity. The synthetic potential of the products has been demonstrated by their conversion to stereodefined alkenes and heterocyclic compounds.

Full text of DOI:10.1021/acs.orglett.1c00452

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Letter
Halogen-Substituted Allenyl Ketones through Ring Opening of
Nonstrained Cycloalkanols
Penglin Wu and Shengming Ma*
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ABSTRACT: An efficient synthesis of halogen-substituted allenyl
ketones via Ag-catalyzed oxidative ring opening of allenyl cyclic
alcohols under mild reaction conditions has been achieved. The
reaction features a wide substrate scope and excellent regiose-
lectivity. The synthetic potential of the products has been
demonstrated by their conversion to stereodefined alkenes and
heterocyclic compounds.
llenes are an important class of molecules because of their
optimize the reaction conditions. First, different mixed solvents
were screened. THF/H2O resulted in no product 3aa (Table 1,
entry 1). Other mixed solvents such as MeCN/H2O, EA/H2O,
and c-hexane/H2O provided the desired product 3aa in 5−
32% yield (Table 1, entries 2−4). It was observed that
toluene/H2O was the best mixed solvent and that DCM/H2O
had almost the same effect (58−60% yields; Table 1, entries 5
and 6). We further reduced the amount of AgNO3, and 20.0
mol % was enough for the reaction (Table 1, entry 7). Then
we tried different silver catalysts such as AgSbF6, AgPF6,
AgBF4, and AgOTs. All of the catalysts provided lower yields of
the desired product 3aa (26−40%; Table 1, entries 8−11).
Subsequently, we also tested some other oxidants such as
TBHP and Na2S2O8 and found that K2S2O8 was still the best
oxidant (Table 1, entries 12 and 13). Next, we observed that
lowering the temperature to 10 °C increased the yield of 3aa to
65% with recovery of 9% of starting material 1a (Table 1, entry
14). Decreasing the temperature further to 0 °C did not
improve the yield of 3aa (60%; Table 1, entry 15), and
increasing the loading of AgNO3 to 24.0 mol % at 10 °C led to
a 67% yield of product 3aa with trace recovery of 1a (Table 1,
entry 16). We also conducted the reaction in the air
atmosphere, and the NMR yield of product 3aa dramatically
decreased to 27% (Table 1, entry 17). Finally, the yield of 3aa
was further improved to 77% when the reaction was carried
out on a 1.0 mmol scale (Table 1, entry 18).
A
unique cumulated double bonds, which are found in
many bioactive natural products and pharmaceuticals.1 Among
various allene derivatives, allenyl ketones are excellent
electrophiles that undergo nucleophilic addition and cycliza-
tion reactions.2 Consequently, much attention has been paid to
synthetic routes for allenyl ketones.3 Oxidations of secondary
2,3-allenols and homopropargylic alcohols are the most
straightforward approaches (Scheme 1a).4 On the other
Scheme 1. Oxidation of Alcohols to Allenyl Ketones
hand, much attention has recently been paid to the catalytic
C−C bond cleavage of nonstrained systems.5,6 Here we wish
to report the oxidative ring-opening reaction of allenyl cyclic
alcohols to afford halogen-substituted allenyl ketones (Scheme
1b).
Received: February 8, 2021
Published: March 18, 2021
In the beginning, we used 1-propadienylcyclohexanol (1a)
as the model substrate and NCS (2a) as the chlorine source to
https://doi.org/10.1021/acs.orglett.1c00452
© 2021 American Chemical Society
Org. Lett. 2021, 23, 2533−2537
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a
Table 1. Optimization of the Reaction Conditions
T
(°C)
yields of 3aa/1a
b
entry
[Ag]
oxidant
solvent
(%)
1
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgSbF6
AgPF6
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
TBHP
Na2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
THF
MeCN
EA
c-hexane
DCM
25
25
25
25
25
25
25
25
25
25
25
25
25
10
0
0/0
5/0
2
3
4
5
6
7
8
9
27/0
32/0
58/0
60/0
58/0
26/6
34/0
37/0
40/0
0/85
38/6
65/9
60/14
67/trace
27/48
77/2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
c
c
c
c
c
c
c
10
11
12
13
14
15
16
17
18
AgBF4
AgOTs
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
c d
,
c d
,
de
,
10
10
10
de f
,
,
de g
,
,
a
The reaction was conducted with 0.2 mmol of 1a, 0.5 equiv of
AgNO3, 2.5 equiv of K2S2O8, and 1.5 equiv of NCS in 0.5 mL of H2O
and 0.5 mL of toluene at 25 °C for 24 h under an Ar atmosphere.
b
c
NMR yields with CH2Br2 as the internal standard. 0.20 equiv of
d
AgNO3 and 1.0 equiv of K2S2O8 were applied. The reaction time was
e
12 h. 0.24 equiv of AgNO3 and 1.2 of equiv K2S2O8 were applied.
f
g
The reaction was conducted in air. 1.0 mmol scale.
With the optimized reaction conditions in hand, the
substrate scope of various nonstrained cycloalkanols 1 with
different halogen sources was investigated (Figure 1). First of
all, we evaluated the ring sizes of cycloalkanols with different
halogen sources. We found that when NCS was used as the
halogen source, cycloalkanols with ring sizes of 5−8 could be
applied, generating 3aa−da smoothly. NBS and even
Selectfluor could be used as the halogen source to afford the
corresponding ketones in moderate yields (3ab−cb, 3ac, 3cc,
and 3dc). Because the C−F bond in saturated systems shows
low surface tension,7 increased lipophilicity of bioavailability,8
high thermal stability,9 and isoelectronic effects to −OH,
−NH2 and −CH3,10 the synthesis of alkyl fluorides is of high
current interest.11 Here we efficiently prepared potentially
useful alkyl fluorides 3ac, 3cc, 3dc, and 3kc with an allenyl
ketone unit, which are difficult to prepare by known methods.
Next, reactions using a wide range of cyclohexanols substituted
with methyl, ethyl, dimethyl, carbonyl, and acetal at the 4-
position led to the formation of the desired products 3ea−ia
and 3eb−ib. Besides, the reactions of 4-allenyltetrahydro-2H-
pyran-4-ol also delivered the desired allene products 3ja and
3jb in 30 and 40% yield, respectively.
a
Figure 1. Substrate scope. Notes: The reaction was conducted with
1.0 mmol of 1, 0.24 equiv of AgNO3, 1.20 equiv of K2S2O8, and 1.5
equiv of NCS (2a) or NBS (2b) or 2.0 equiv of Selectfluor (2c) in 2.5
mL of H2O and 2.5 mL of DCM at 10 °C for 12 h under an Ar
atmosphere. Numbers in parentheses are the yields of the recovered
Furthermore, with nonsymmetrical examples, excellent
selectivity was observed for the C−C bond cleavage in the
α-substituted substrates, affording the products 3ka, 3kb, 3kc,
and 3lb in decent yields exclusively. High regioselectivity was
observed for the bridged bicyclic substrate 1m, affording 3ma
and 3mb as the main products (3ma:3ma′ = 96:4, 3mb:3mb′
b
starting cyclohexanols 1. 2.5 mL of toluene was used instead of 2.5
c
mL of DCM. With 0.40 equiv of AgNO3 and 2.0 equiv of K2S2O8.
dWith 0.50 equiv of AgNO3 and 2.5 equiv of K2S2O8. eWith 0.50 equiv
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To gain insight into the mechanism, we carried out some
control experiments. First of all, for the ring-opening
chlorination reactions, control experiments revealed that the
combination of AgNO3, K2S2O8, and H2O was necessary
(Scheme 3a). Water is believed to increase the solubility of
Figure 1. continued
of AgNO3. fThe reaction was run on a 0.2 mmol scale. The reaction
g
time was 14 h. hThe reaction time was 13 h. With 1.5 equiv of
i
j
Selectfluor. The reaction was conducted with 0.5 mmol of 1p, 0.50
equiv of AgNO3, 1.20 equiv of K2S2O8, and 1.5 equiv of 2a in 1.2 mL
of H2O and 1.2 mL of DCM at 10 °C for 24 h under an Ar
Scheme 3. Mechanistic Studies
k
atmosphere. The reaction was conducted with 0.2 mmol of 1p, 0.50
equiv of AgNO3, 1.20 equiv of K2S2O8, and 1.5 equiv of NBS (2b) in
0.5 mL of H2O and 0.5 mL of DCM at 10 °C for 36 h under an Ar
atmosphere.
= 90:10; Figure 1). Even the reaction of β-substituted substrate
3n formed 3na and 3nb with high selectivity with respect to
3na′ and 3nb′.
To demonstrate the synthetic utility and practicality of the
method, we conducted the gram-scale reaction of 1a with NBS
under standard conditions, which afforded 1.4464 g of 3ab in
65% yield. The synthetic potential of this product was also
demonstrated (Scheme 2). Product 3ab could be reduced with
a
Scheme 2. Representative Synthetic Potential of 3ab
K2S2O8 in the reaction mixture. Besides, if a capturing agent
such as NCS was not added, we did not observe ring expansion
products, and the reaction led to a complicated result. We
found that the reaction was suppressed when 2.0 equiv of
TEMPO was added under the standard conditions (Scheme
3b). In addition, the desired product 12 was obtained when
1,4-benzoquinone was used as a radical trapper (Scheme 3c).18
These results indicated the involvement of a radical pathway in
the reaction.
On the basis of these results, the plausible mechanism shown
in Scheme 4 is proposed. First, AgI is oxidized by K2S2O8 to
generate the AgII species.19 Subsequently, cycloalkanol 1 is
oxidized by the metastable AgII species to give cycloalkoxy
radical intermediate I. β-Scission of cycloalkoxy radical
intermediate I generates two ring-opened alkyl radical
intermediates, II and II′, both of which are then intercepted
a
Reaction conditions: (a) 3ab (0.2 mmol), LiAlH4 (0.5 equiv), Et2O,
0 °C, then rt, 12 h; (b) 3ab (0.2 mmol), NaI (5.0 equiv), acetone, 70
°C, 12 h; (c) 3ab (0.2 mmol), AgBF4 (0.4 equiv), CH3CN, 100 °C,
12 h; (d) 3ab (0.2 mmol), LiI (1.2 equiv), AcOH, 25 °C, 3 h; (e) 3ab
(0.24 mmol), aniline (0.2 mmol), Na2CO3 (0.1 M), rt, 11 h; (f) 3ab
(0.2 mmol), 4-bromophenol (1.0 equiv), K2CO3 (3.0 equiv), acetone,
65 °C, 12 h; (g) 3ab (0.24 mmol), diethyl malonate (0.2 mmol),
K2CO3 (0.2 equiv), EtOH, 60 °C, 12 h; (h) 3ab (0.2 mmol), 1,3-
cyclohexanedione (1.0 equiv), Ph3P (0.1 equiv), toluene, 70 °C, 12 h.
Scheme 4. Proposed Mechanism
LiAlH4 to provide secondary alcohol 4 in 77% yield.12 The
bromide could be converted to iodide 5 in 95% yield.6j The
cyclization of 3ab worked smoothly to provide furan 6 in 70%
yield.13 Alternatively, α-allenyl ketone 3ab is a very good
Michael acceptor for transformations such as 1,4-Michael
addition with LiI to generate β,γ-unsaturated enone 714 and
1,4-addition with aniline or 4-bromophenol to provide α,β-
unsaturated ketones Z-8 and E-9 in high to excellent yields.15
3ab could also be readily converted to α-pyrone derivative 10
with diethyl malonate.16 The tandem reaction of 3ab and 1,3-
cyclohexanedione constructed heterocycle 11 in 80% yield via
triphenylphosphine-catalyzed umpolung addition and intra-
molecular conjugate addition.17
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Cyclization Reaction of 2,3-Allenoic Acids and 1,2-Allenyl Ketones.
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by NCS, NBS, or Selectfluor to eventually afford the halogen-
substituted allenyl ketones 3 and 3′, respectively.
In summary, we have developed an efficient procedure for
the preparation of halogen-substituted allenyl ketones through
silver-catalyzed oxidative ring opening of allenyl cycloalkanols.
A wide range of products with substituents at different
positions have been synthesized. These allenyl ketones can be
easily converted to other useful molecules. Preliminary control
experiments indicated a radical pathway. Further studies in this
area are being conducted in this laboratory.
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00452.
Experimental details and data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
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Shengming Ma − Research Center for Molecular Recognition
and Synthesis, Department of Chemistry, Fudan University,
Shanghai 200433, P. R. China; State Key Laboratory of
Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai 200032,
P. R. China; orcid.org/0000-0002-2866-2431;
Email: masm@sioc.ac.cn
Author
Penglin Wu − Research Center for Molecular Recognition and
Synthesis, Department of Chemistry, Fudan University,
Shanghai 200433, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00452
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation of China (21690063) is greatly appreciated. We
thank Mr. Junzhe Xiao in this group for reproducing the results
for 3cb, 3ja, and 3na in Figure 1.
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