Practical synthesis of α,β-Alkynyl ketones by oxidative alkynylation of aldehydes with hypervalent alkynyliodine reagents

Article abstract of DOI:10.1246/cl.200131

A practical, metal-free carbonyl C(sp²)H oxidative alkynylation of aldehydes with hypervalent alkynyliodine reagents without the use of any catalysts is described for the synthesis of various α,β-alkynyl ketones. Here, two different methods have been developed where limiting reagents or substrates can be switched, and adopted according to the valuableness of aldehyde substrates or hypervalent alkynyliodine reagents. These reactions proceed with a broad substrate scope and high functional-group compatibility.

Full text of DOI:10.1246/cl.200131

Advance Publication Cover Page
Practical Synthesis of α,β-Alkynyl Ketones by Oxidative Alkynylation of Aldehydes
with Hypervalent Alkynyliodine Reagents
Saori Tsuzuki, Ryu Sakamoto, and Keiji Maruoka*
Advance Publication on the web March 20, 2020
doi:10.1246/cl.200131
© 2020 The Chemical Society of Japan
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Publication manuscripts.

1
Practical Synthesis of
,
a b
-Alkynyl Ketones by Oxidative Alkynylation of Aldehydes
with Hypervalent Alkynyliodine Reagents
Saori Tsuzuki, 1 Ryu Sakamoto, 1 and Keiji Maruoka*1-3
1Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502
2 Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo, Kyoto 606-8501
3School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou 510006, China
E-mail: maruoka@kuchem.kyoto-u.ac.jp
1
2
3
4
5
6
7
8
9
A practical, metal-free carbonyl C(sp2)–H oxidative
47 furnish 5-methyl-1-phenylhex-1-yn-3-one (2a) in 23% yield
alkynylation of aldehydes with hypervalent alkynyliodine
reagents without the use of any catalysts is described for the
synthesis of various a,b-alkynyl ketones. Here, two
different methods have been developed where limiting
reagents or substrates can be switched each other, and
adopted them according to the valuableness of aldehyde
substrates or hypervalent alkynyliodine reagents. These
reactions proceed with a broad substrate scope and high
48 (entry 1). In contrast, switching a hypervalent iodine reagent
49 from 1a to bis(trifluoromethyl) derivative 1b under
50 otherwise similar heating condition afforded 2a in much
51 better yield (entry 2). Use of 3 or 1.2 equiv of aldehydes
52 lowered the yields of 2a (entry 3). The solvent effect is
53 found to be very critical (entries 2 and 4-8). Though THF
54 and DMF as solvent are not acceptable for this
55 transformation (entries 4 and 5), MeCN and DCE afforded
56 higher yields of 2a (entries 7 and 8). The reaction
57 temperature and time are somewhat important, and the use
58 of 80 °C for 12 h gave the highest yield of 2a (entry 9). The
59 reaction proceeded smoothly without irradiation of light
60 (entry 10). Again, the use of 1a under similar reaction
61 condition resulted in much lower yield (entry 11). Switching
62 to other hypervalent alkynyliodine reagents 1c and 1d
63 lowered the chemical yields (entries 12 and 13). Use of
64 longer reaction time, higher or lower temperature, and
65 higher concentration (1.0 M vs. 0.5 M) of the solution gave
66 rise to the inferior results (entries 14~17).
10 functional-group compatibility.
11 Keywords: Alkynyl ketone, Hypervalent alkynyliodine
12 reagent, Metal-free
13
a,b-Alkynyl ketones are important structural units in
14 various bioactive molecules and materials.1,2 Accordingly,
15 there are numerous approaches so far for the synthesis of
16 such a,b-alkynyl ketones.3 Classical and traditional
17 approaches have involved the direct nucleophilic addition of
18 alkynyl anions to carbonyl derivatives.1c,2a,2b,2d,4 More
19 recently, some radical approaches involving oxidative
20 alkynylation of aldehydes with hypervalent 1-alkynyl-1,2-
67
21 benziodoxol-3(1H)-one
under
the
influence
of
68 Table 1. Optimization of the oxidative alkynylation of aldehydes with
22 stoichiometric tert-butyl hydroperoxide or photoredox
23 catalysis.5-7 In this context, we are interested in the
24 possibility of developing a practical and atom-economical
25 approach to a,b-alkynyl ketones based on the oxidative
26 alkynylation of aldehydes with hypervalent alkynyliodine
27 reagents without the use of any other reagents or catalysts.
28 Here we wish to report our initial study on this subject, in
29 which we developed two different methods, based on the
30 use of either 1 equiv of aldehyde substrate or 1 equiv of
31 alkynyliodine reagents (Scheme 1). These two methods
32 would be complementary and necessary, if either
33 alkynyliodine reagent or aldehyde substrate would be very
34 valuable.
35
36
37
38
39
40
41
69
hypervalent iodine reagenta
O
O
solvent
[ I ]
70
71
72
73
74
75
76
77
78
79
80
81
Ph
I
+
H
80~100 °C
4~24 h
1
(5 equiv)
Ph
2a
Ph
O
Ph
Ph
I
O
CF3
CF3
O
1a
1b
I
OTf
Ph
I
O
CF3
CF2CF3
1d
1c
R1
I O
Condition
(°C, h)
b
Entry
Reagent
Solvent
Yield (%)
O
R1
I O
O
O
R2
heat
method [1]
H
1
2
3
4
5
6
7
8
9
1a
1b
1b
1b
1b
1b
1b
1b
1b
benzene
benzene
benzene
THF
DMF
PhCl
MeCN
DCE
DCE
80, 4
80, 4
80, 4
80, 4
80, 4
80, 4
80, 4
80, 4
80, 12
23
51
R2
(1 equiv)
H
R2
heat
method [2]
R1
c
d
(1 equiv)
49, 39
12
34
57
67
68
42
43
Scheme 1. Two different approaches for the synthesis of
a,b-alkynyl ketones.
44
Initially, reaction of excess 3-methylbutanal (5 equiv)
45 with 1 equiv of 1-[phenylethynyl]-1,2-benziodoxol-3(1H)-
72 (70)
46 one (1a) was carried out in benzene at 80 °C for 4 h to

2
48 aReaction conditions unless otherwise noted: aldehyde (1.0 mmol),
e
10
11
12
13
14
15
16
17
1b
1a
1c
1d
1b
1b
1b
1b
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
80, 12
80, 12
80, 12
80, 12
80, 24
50, 24
100, 12
80, 12
69
49 reagent 1b (0.2 mmol) in solvent (0.5 M) under indicated condition. bAt
48
33
4
63
57
59
50 50 °C for 24 h.
51
52
53
The scope of the oxidative alkynylation with respect to
54 alkynyliodine reagents (1) is summarized in Table 3. para-
55 Tolyl-, para-bromophenyl- and mesitylalkynyliodine
56 reagents 1e~g as well as triisopropyisilylalkynyliodine
57 reagent 1h can be successfully utilized for the oxidative
58 alkynylation of 3-methylbutanal. However, attempted
59 reaction of cyclohexanecarbaldehyde with ethynyliodine
60 reagent 1 (R1 = H) was unsuccessful.
f
57
1
2
3
4
5
6
7
8
9
aReaction conditions unless otherwise noted: 3-methylbutanal (1 mmol),
reagent 1 (0.2 mmol) in solvent (0.5 M) under indicated condition. bThe
yield was determined by 1H NMR spectroscopy using 1,1,2,2-
tetrachloroethane as the internal standard. Isolated yield is given in
parentheses. cUse of 3 equiv of aldehyde. dUse of 1.2 equiv of aldehyde.
eUnder dark atmosphere. fUse of 1.0 M solution.
61
62
63
Table 3. Scope of alkynylation reagentsa
With the optimized conditions in hand, we
64
65
66
67
68
69
70
71
10 subsequently examined the scope of the oxidative
11 alkynylation with 1b with respect to various aldehyde
12 substrates (2) as shown in Table 2. Not only prim-alkyl
13 substituted aldehydes but also sec- and tert-alkyl substituted
14 aldehydes are employable. In case of pivalaldehyde under
15 the standard condition (80 °C, 12 h), decarbonylation took
16 place before the C–C bond formation, thereby giving tert-
17 butyl phenyl acetylene (3e) in 51% yield.6b,8 Fortunately, the
18 similar reaction at 50 °C could totally suppress the
19 undesired decarbonylation to furnish the desired 2e in
20 moderate yield. In addition, heterocyclic aldehydes and
21 aromatic aldehydes afforded the corresponding alkynylation
22 products in good yields. In case of benzaldehyde, 2i was
23 obtained with 41% recovery of 1b by NMR analysis.
24
Entry
Reagent 1
Product 2
Yield (%)
1
2
1e
1f
1g
1h
2k
2l
2m
2n
62
54
63
51
b
3
4
72
73 aReaction conditions unless otherwise noted: 3-methylbutanal (1.0
25
Table 2. Substrate scopea
74 mmol), reagent 1 (0.2 mmol) in solvent (0.5 M) under indicated
75 condition. bReaction was conducted in 0.1 mmol scale.
76
77
78
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
Although aldehyde substrates are generally abundant
79 and readily available, the use of excess amount of substrates
80 would be inconvenient in certain case such as the late-stage
81 functionalization of complex molecules. Thus, we also
82 developed the other method, based on the use of 1 equiv of
83 aldehyde substrate under otherwise similar reaction
84 conditions. Indeed, the reaction of 3-methylbutanal (1
85 equiv) with 1.2 equiv of 1b was carried out in DCE (2.5 M)
86 at 80 °C for 4 h to furnish 5-methyl-1-phenylhex-1-yn-3-one
87 (2a) in 62% yield. Use of excess 1b (2 equiv) did not affect
88 the yield. It should be noted that the use of a 2.5 M solution
89 is found to be crucial, and attempted use of a more dilute
90 solution (0.5 M) lowered the yield (39%) of 2a. With this
91 reaction condition at hand, several different aldehydes are
92 susceptible to the oxidative alkynylation with 1b (1.2 equiv)
93 as shown in Table 4 (See also the Supporting Information).
94
95
96
97
98

3
1
Table 4. Substrate scopea
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
2
3
4
5
6
7
8
9
Ph
+
I
O
O
O
DCE
CF3
CF3
R2
R2
(1 equiv)
H
80 °C, 4 h
2
Ph
1b
O
O
Ph
Ph
Ph
2a, 62%
2b, 35%
10
11
12
13
14
15
O
O
Ph
Ph
2d, 43%
2i, 35%
16 aReaction conditions unless otherwise noted: aldehyde (0.2 mmol),
17 reagent 1b (0.24 mmol) in solvent (2.5 M) under indicated condition.
73
18
19
20
74 Scheme 3. Control experiments with (a) TEMPO and (b) o-
75
76
77
phthalaldehyde.
Furthermore, the synthetic utility of this approach was
21 demonstrated by the reaction of hypervalent alkynyliodine
22 reagent 1b with estrone-derived substrate 4, affording the
23 desired product 2o in 48% yield (Scheme 2). This result
24 indicates that our method is potentially applicable to the
25 late-stage functionalization in the total synthesis of bioactive
26 molecules.
27
28
29
30
31
32
33
34
35
36
37
In conclusion, we have developed two different ways
78 of preparing various a,b-alkynyl ketones from aldehydes
79 with hypervalent alkynyliodine reagents in the absence of
80 any catalysts under mild, metal-free conditions. These
81 methods can be properly used depending on the
82 valuableness of aldehyde substrates and alkynyliodine
83 reagents. The generality of these approaches was well
84 demonstrated with various types of aldehydes, including
85 aliphatic (prim-, sec-, and tert-alkyl) aldehydes and aromatic
86 aldehydes. Further investigations into the applications of
87 such a practical, metal-free oxidative alkynylation strategy
88 for various aldehydes for the physiologically active
89 compounds are currently in progress in our laboratory.
90
O
H
Ph
I
O
+
CF3
CF3
H
H
O
H
O
4
1b (2 equiv)
Ph
H
H
91
DCE (2.0 M)
80 °C, 12 h
O
92 This work was supported by JSPS KAKENHI Grant
93 Number JP26220803 and JP17H06450 (Hybrid Catalysis).
94
H
2o, 48%
38 Scheme 2. Synthetic application using estrone derivative 4.
95 Supporting
Information
is
available
on
96 http://dx.doi.org/10.1246/cl.******.
97 References and Notes
39
In order to elucidate the reaction mechanism, we
40 carried out several control experiments. When the reaction
41 of 3-methylbutanal (5 equiv) with 1 equiv of 1b was
42 executed in DCE at 80 °C for 9 h in the presence of a radical
43 scavenger, 2,2,6,6-tetramethylpiperidin-1-yl)oxy (TEMPO),
44 the alkynylation was totally inhibited, and 1b was recovered
45 in >90% yield (Scheme 3a). This result implies some radical
46 intermediates are most likely participated in this
47 alkynylation. In addition, a solution of o-phthalaldehyde (5
48 equiv) in DCE was treated with 1 equiv of 1b at 80 °C to
49 furnish cyclization product 2p, implying the intervention of
50 acyl radical intermediate 5 (Scheme 3b). We assume that the
51 coordination of aldehyde carbonyl to electrophilic
52 iodine(III) reagent 1b might accelerate the acyl radical
53 formation with trace amounts of oxygen gas in a reaction
54 system.
98
99
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6
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8
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