Synthesis of Ketones through Microwave Irradiation Promoted Metal-Free Alkylation of Aldehydes by Activation of C(sp3)-H Bond

Article abstract of DOI:10.1021/acs.joc.5b01824

In this paper, a novel methodology for the synthesis of ketones via microwave irradiation promoted direct alkylation of aldehydes by activation of the inert C(sp³)-H bond has been developed. Notably, the reactions were accomplished under metal-free conditions and used commercially available aldehydes and cycloalkanes as substrates without prefunctionalization. By using this novel method, an alternative synthetic approach toward the key intermediates for the preparation of the pharmaceutically valuable oxaspiroketone derivatives was successfully established.

Full text of DOI:10.1021/acs.joc.5b01824

Subscriber access provided by Mount Allison University | Libraries and Archives
Article
Synthesis of Ketones through Microwave Irradiation Promoted
Metal-free Alkylation of Aldehydes by Activation of C(sp3)-H Bond
Xinying Zhang, Zhangxin Wang, Xuesen Fan, and Jianji Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01824 • Publication Date (Web): 12 Oct 2015
Downloaded from http://pubs.acs.org on October 13, 2015
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 25
The Journal of Organic Chemistry
1
2
3
4
5
Synthesis of Ketones through Microwave Irradiation Promoted Metal-free
6
7
8
Alkylation of Aldehydes by Activation of C(sp3)−H Bond
9
Xinying Zhang*, Zhangxin Wang, Xuesen Fan*, and Jianji Wang
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Henan
Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical
Media and Reactions, Ministry of Education, Henan Normal University, Xinxiang, Henan
453007, China
E-mail: xinyingzhang@htu.cn; xuesen.fan@htu.cn
Abstract: In this paper, a novel methodology for the synthesis of ketones via microwave
irradiation promoted direct alkylation of aldehydes by activation of the inert C(sp3)−H bond has
been developed. Notably, the reactions were accomplished under metal-free conditions and used
commercially available aldehydes and cycloalkanes as substrates without pre-functionalization.
By using this novel method, an alternative synthetic approach toward the key intermediates for
the preparation of the pharmaceutically valuable oxaspiroketone derivatives was successfully
established.
INTRODUCTION
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 25
1
2
3
4
5
6
7
8
9
Ketones constitute one of the most important classes of organic compounds. The significance of
ketones has stimulated extensive studies to develop novel methods for their preparation.1 As
aldehyde is structurally close to ketone and there are numerous aldehydes commercially
available or readily obtainable, ketone has been frequently prepared from aldehyde in both
academic and industrial arena. In most cases, this protocol is realized through an initial addition
of organometallic agent to aldehyde followed by an oxidation of the alcohol intermediate
(Scheme 1, (a)).2 While this approach is generally reliable and efficient, it often suffers from
tedious operation procedures and the necessity of using air/moisture sensitive organometallic
reagents. Therefore, to develop new synthetic methods to prepare ketones from aldehydes
through a one-step procedure without using labile organometallic reagents remains an attractive
but still challenging task (Scheme 1, (b)).3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. One- vs Two-step Synthesis of Ketone from Aldehyde
Meanwhile, the development of more sustainable transformations is an extensively pursued
objective for synthetic community. In this regard, an appealing strategy to replace the existing
tedious multi-step protocols to meet the criteria of both atom economy and step economy is
through C−H activation as this strategy usually uses the abundant and cheap hydrocarbon
compounds as the starting materials without “pre-activation”.4 Among various versions of C−H
activation and the following functionalizations developed so far, C−C bond formation via
C(sp3)−H activation deserves special attention as alkanes could be readily converted into the
corresponding alkyl radicals in the presence of peroxide or other radical inductors.5,6 In this
ACS Paragon Plus Environment

Page 3 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
aspect, Zhu recently developed a metal-free cascade alkylation of N-phenyl-N-tosylmethacryl
amide with simple alkanes based on a radical process.7 Wei reported a novel copper-catalyzed
direct alkenylation of simple alkanes with styrenes to give (E)-alkyl substituted alkenes (Scheme
2, (a)).8 Han revealed a metal-free oxidative C(sp3)−H bond activation of alkanes and conjugate
addition to chromones (Scheme 2, (b)).9 Han has also developed a novel synthesis of cycloallyl
esters from cycloalkanes and aromatic aldehydes via copper-catalyzed C(sp3)−H bond activation
(Scheme 2, (c)).10 Promoted by those pioneering studies and based on the fact that radical
processes are valued for their excellent functional group tolerance, and inherent ability to be
integrated into one-pot cascade processes, we have developed a novel synthesis of aryl
cycloalkyl ketones via direct alkylation of aryl aldehydes with simple alkanes in the presence of
peroxide under microwave irradiation (MWI) through a radical pathway (Scheme 2, (d)). Herein,
we wish to report the results of this study.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2. Some Radical Reactions of Cyclohexane
RESULTS AND DISCUSSION
Our study was initiated by treating benzaldehyde (1a) with cyclohexane (2a) in the presence
o
of di-tert-butyl peroxide (TBP) at 120 C for 24 h. However, the formation of the expected
cyclohexyl(phenyl)methanone (3a) was not observed (Table 1, entry 1). When the reaction
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 25
1
2
3
4
5
o
temperature was elevated to 140 C, 3a could be obtained in a yield of 5% (entry 2). Further
6
7
8
9
studies found that the efficiency improved along with increasing amounts of TBP (entries 3-5).
Next, azodiisobutyronitrile (AIBN), benzoyl peroxide (BPO), tert-butyl hydroperoxide (TBHP)
and dicumyl peroxide (DCP) were also tried. However, they were found to be less effective than
TBP (entries 6-9). Considering the fact that previous studies have identified some beneficial
effects of copper salts on the radical reactions of alkanes,11 we then tried a combination of TBP
with CuBr, or Cu(OTf)2 as the inductor. Unfortunately, the yield of 3a did not improve in both
cases (entries 10-11). Similarly disappointing was the addition of tetrabutylammonium iodide
(TBAI) as an additive (entry 12). Inspired by the fact that MWI has been used as an efficient
heating method in a broad variety of chemical reactions and there appear to be good grounds to
expect a synergistic alliance of homolytic and MWI methods as reviewed by McBurney,12 the
reaction of 1a and 2a was then tried under MWI conditions. We were very pleased to find that
the yield of 3a could be improved to 58% when the reaction was run in the presence of TBP
under MWI at 180 oC for 1 h (entry 16). Lower temperatures, shorter/longer reaction period, or
using AIBN, BPO, TBHP, or DCP to replace TBP, led to decreased yield (entries 13-22). In
order to study the effect of metal salts on this reaction under MWI, it was also carried out in the
presence of Cu(OTf)2, CuBr2, CuBr, CuI, FeCl2·4H2O,13 or FeCl3·6H2O. However, no obvious
improvement in the yield of 3a was observed (entries 23-28). It was also found that a
combination of TBHP with FeCl2·4H2O did not give positive result (entry 29).13 Moreover, 365
nm cold light-emitting diodes (LED) were used to irradiate the reaction mixture for 1.5 h. It was
found that under these conditions, the reaction did occur with or without TBP. However, the
yields were relatively poor compared with those obtained under MWI (entries 30, 31). In
summary of our optimization study, 3a could be obtained in 58% yield by treating 1a with 2a in
the presence of TBP under MWI at 180 oC for 1 h.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

Page 5 of 25
The Journal of Organic Chemistry
1
2
3
4
Table 1. Optimization for the Synthesis of 3a a
O
5
6
7
8
CHO
conditions
+
2a
3a
1a
9
Entry
1
Inductor (molar ratio)
TBP (2)
Irradiation
T/°C
120
140
140
140
140
140
140
140
140
140
140
140
120
140
160
180
160
160
160
160
180
180
180
180
180
180
180
180
t/h
24
24
24
24
24
24
24
24
24
24
24
24
1
Yield (%) b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
-
-
5
2
TBP (2)
-
3
TBP (3)
-
8
4
TBP (4)
-
12
12
-
5
TBP (6)
-
6
AIBN (4)
-
7
BPO (4)
-
6
8
TBHP (4)
-
-
9
DCP(4)
-
7
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
TBP(4)+CuBr(0.2)
TBP(4)+Cu(OTf)2(0.2)
TBP(4)+TBAI(0.2)
TBP (4)
-
5
-
5
-
11
trace
26
39
58
0
MWI
MWI
MWI
MWI
MWI
MWI
MWI
MWI
MWI
MWI
MWI
MWI
MWI
MWI
MWI
MWI
TBP (4)
1
TBP (4)
1
TBP (4)
1
AIBN (4)
1
BPO (4)
1
32
0
TBHP (4)
1
DCP(4)
1
28
40
54
51
57
58
52
59
56
TBP (4)
0.5
1.5
1
TBP (4)
TBP(4)+Cu(OTf)2(0.2)
TBP(4)+CuBr2(0.2)
TBP(4)+CuBr(0.2)
TBP(4)+CuI(0.2)
1
1
1
TBP(4)+ FeCl2·4H2O(0.2)
TBP(4)+ FeCl3·6H2O (0.2)
1
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 25
1
2
3
4
5
6
7
8
9
29
30
31
TBHP(4)+ FeCl2·4H2O(0.2)
MWI
UV c
UV c
180
rt
1
-
15
8
TBP(4)
-
1.5
rt
1.5
a Reaction conditions: 1a (0.5 mmol), 2a (10 mL), N2. b Isolated yield. c Under 365 nm cold
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
light-emitting diodes (LED).
With the optimized reaction conditions in hand, we then studied the scope of this ketone
forming reaction. Firstly, different aryl aldehydes were tested by using cyclohexane (2a) as a
model substrate. The results listed in Table 2 showed that aldehydes bearing various functional
groups including methyl, methoxy, fluoro, chloro, bromo, and trifluoromethyl on the phenyl
ring took part in this reaction smoothly to give the expected ketone products in moderate yields.
It was noted that substrates with electron-donating group (EDG) gave higher yield than those
bearing electron-withdrawing group (EWG). The relatively lower yield of 3l indicated that steric
hindrance might also play a role. Notably, halide groups were well compatible with the reaction
conditions to allow further structural elaboration of the ketone products.
Table 2. Substrate Scope for the Preparation of 3 (I) a,b
3a, 58%
3b, 62%
3f, 66%
3j, 36%
3c, 41%
3g, 45%
3k, 64%
3d, 42%
3h, 48%
O
H3C
3e, 57%
H3CO
O
H3CO
CH3
3i, 46%
3l, 51%
a Reaction conditions: 1 (0.5 mmol), 2a (10 mL), TBP (2 mmol), MWI, 180 C, N2, 1
h. b Isolated yield.
o
ACS Paragon Plus Environment

Page 7 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Next, the alkane substrate was extended to cyclopentane (2b). It turned out that the reactions
of 2b with aryl aldehydes bearing various functional groups on the phenyl ring proceeded
smoothly to give the corresponding aryl cyclopentyl ketones (3m-3v, Table 3) in moderate
yields. Similar to those of 2a, reactions of 2b with aryl aldehydes bearing EDG on the phenyl
ring were generally more efficient than those bearing EWG. Furthermore, cycloheptane (2c) and
cyclooctane (2d) were also tried, and they took part in this ketone forming reaction smoothly to
give products 3w-3bb with similar efficiency as those of 2a and 2b.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 3. Substrate Scope for the Preparation of 3 (II) a,b
3m, 56%
3n, 61%
3r, 38%
3o, 56%
3s, 43%
3p, 63%
3t, 44%
O
Cl
3q, 39%
3u, 44%
3y, 40%
3v, 62%
3z, 50%
3w, 47%
3aa, 58%
3x, 53%
3bb, 46%
o
a Reaction conditions: 1 (0.5 mmol), 2 (10 mL), TBP (2 mmol), MWI, 180 C, N2, 1
h. b Isolated yield.
Furthermore, the reaction of n-hexane (2e) as an example of acyclic alkane with 4-methoxy
benzaldehyde (1f) was also tried. It turned out that the ketone forming reaction did occur albeit
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 25
1
2
3
4
5
6
7
8
9
three regio-isomers were obtained as shown in Scheme 3. From these results, it was concluded
that the activity of 2°-H toward acylation was much higher than that of 1°-H. The slightly higher
yield of C2 acylation product compared with that of C3 acylation product should be an
inflection of the steric effect.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. The reaction of 4-methoxybenzaldehyde with n-hexane
As a further aspect, it has been reported that 3H-spiro[benzofuran-2,1'-cyclohexan]-3-one (H,
Scheme 4) is as a key building unit of potential drugs for the treatment of Alzheimer’s disease.14
Recent studies revealed that this oxaspiroketone derivative could be prepared through the
triflation of 2-hydroxyphenyl cyclohexyl ketone (F) followed by an intramolecular triflate
migration and ring closure of the in situ formed enol triflate intermediate.15 As a key
intermediate, F was prepared by reacting Weinreb amide D, derived from cyclohexyl carboxylic
acid (B), with organometallic reagent C obtained from 2-bromomethoxybenzene (A). While this
elegant protocol is currently used by the drug development teams as an efficient and reliable
methodology, its sustainability could be compromised by limited atom- and step-economy as the
preparation of F involved a highly reactive organometallic reagent and there were a lot of atoms
of the substrates not assembled into F.
Scheme 4. Literature Procedure Leading to Oxaspiroketone
ACS Paragon Plus Environment

Page 9 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
With the aim to develop a more sustainable synthetic approach toward 2-hydroxyphenyl
cyclohexyl ketones by taking advantage of the ketone formation method developed in this paper,
2-hydroxybenzaldehyde (1m) was treated with 2a under the standard reaction conditions (Table
1, entry 16). To our delight, the reaction afforded 2-hydroxyphenylcyclohexyl methanone (3ff)
in a yield of 45% (Scheme 5). Following study revealed that 5-bromo-2-hydroxybenzaldehyde
(1n) was an equally suitable substrate to give (5-bromo-2-hydroxyphenyl)(cyclohexyl)
methanone (3gg) in 43% yield. As a further aspect, 1m and 1n were found to be also able to
react with 2b to afford the desired 2-hydroxyphenylcyclopentylmethanone (3hh) and
(5-bromo-2-hydroxyphenyl)(cyclopentyl)methanone (3ii) in yields of 40% and 41%,
respectively.
Scheme 5. An Alternative Procedure for the Preparation of 2-Hydroxyphenyl Ketone
To get some insight into the mechanism of this aldehyde alkylation process, some control
experiments were carried out. Firstly, 2,2,6,6-tetramethylpiperidine oxide (TEMPO) as a radical
scavenger was added in the reaction of 4-methoxybenzaldehyde (1f) with cyclohexane (2a).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 25
1
2
3
4
5
6
7
8
9
Under this circumstance, the aldehyde alkylation process was completely inhibited and the
formation of 3f was not observed (Scheme 6). This study suggests that the formation of 3f
should involve a single electron transfer (SET) process.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 6. Control Experiment (I)
Secondly, an intermolecular competing kinetic isotope effect (KIE) experiment was conducted
by treating 4-methoxybenzaldehyde (1f) with a mixture of cyclohexane (2a) and
[D]-cyclohexane ([D]-2a) under standard conditions as shown in Scheme 7. Consequently, a
1
significant KIE was observed with kH/kD = 4.56 (the KIE value was determined based on H
NMR spectroscopy studies through analyzing the ratio of 3f and [D]-3f). This result indicates
that the C(sp3)−H bond cleavage may be one of the rate-determining steps of this ketone
formation reaction.
Scheme 7. Control Experiment (II)
Based on the above results and previous reports,7-10 a plausible mechanism for the formation
of 3a from the reaction of 1a and 2a was proposed in Scheme 8. Initially, homolysis of the O−O
bond in TBP under the assistance of MWI generates the tert-butyoxyl radical. The following
hydrogen abstraction of 2a by the tert-butyoxyl radical forms the cyclohexyl radical and
ACS Paragon Plus Environment

Page 11 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
tert-butyl alcohol. Next, addition of the cyclohexyl radical onto the carbonyl group of 1a leads
to the formation of alcohoxyl radical I. Finally, abstraction of a hydrogen radical from I by
another tert-butyoxyl radical gives the ketone product 3a.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 8. Plausible Mechanism for the Formation of 3a
As shown in Tables 1~3, an excess amount of cycloalkane (2) is usually utilized to act as both
substrate and reaction medium in the ketone formation reactions. Therefore, how well to recover
and reuse the excess cycloalkane is crucial in determining the sustainability of this protocol. To
check the reusability of the excess cyclohexane, the resulting mixture from the reaction of 1a
(0.5 mmol) and 2a (10 mL) was distillated under reduced pressure to recover 9.2 mL of 2a.
Then, the recovered 2a was treated with 1a (0.5 mmol) under standard conditions to give 3a in a
yield of 57%. The recycle test was then carried out for 3 more times, and with the recovered 2a
(8.5 mL, 7.6 mL, 6.6 mL), 3a was obtained in yields of 55%, 56%, and 53%, respectively.
Finally, in order to showcase the applicability of this ketone forming reaction, a larger scale
preparation of cyclohexyl(4-methoxyphenyl)methanone (3f) was carried out. Thus, 5 mmol of 1f
(0.68 g) was treated with cyclohexane (2a, 55 mL) under standard conditions. Upon completion,
the reaction mixture was distillated under reduced pressure to recover 2a. From the residue, 3f
was separated in a yield of 62%. Furthermore, when the reaction was run with an enlarged scale
of 10 mmol (1.36g of 1f), 3f could be obtained in a yield of 55%.
CONCLUSION
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 25
1
2
3
4
5
6
7
8
9
In conclusion, a novel methodology for the synthesis of ketones via direct alkylation of
aldehydes with simple alkanes by activation of the inert C(sp3)−H bond has been developed in
this paper. Notably, the ketone formation reactions were realized under metal-free conditions
and used commercially available aldehydes and alkanes without pre-functionalization.
Interestingly, by using this method, an alternative synthetic approach toward the key
intermediates for the preparation of the pharmaceutically valuable oxaspiroketone derivatives
was successfully established. With advantages such as economical starting materials, excellent
atom-economy, and applicability to a wide range of substrates, we foresee this protocol to be
useful in expanding the scaffold space of ketone derivatives as versatile intermediates in
synthetic chemistry.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
EXPERIMENTAL SECTION
General Methods
1
13
All the commercial reagents and solvents were used without further purification. H and C
NMR spectra were determined as CDCl3 solutions. Chemical shifts were expressed in parts per
million (δ) downfield from the internal standard tetramethylsilane and were reported as s
(singlet), d (doublet), t (triplet), quint (quintuplet), dd (doublet of doublet), tt (triplet of triplet),
m (multiplet), etc. The coupling constants J were given in Hz. High resolution mass spectra
(HRMS) were performed on a time-of-flight (microTOF) mass spectrometer. All reactions were
monitored by thin-layer chromatography (TLC) using silica gel plates (silica gel 60 F254 0.25
mm) and components were visualized by observation under UV light (254 and 365 nm). MWI
promoted reactions were performed in a commercial microwave reactor (XH-200A, Beijing
Xianghu Science and Technology Development Co. Ltd, Beijing, China).
ACS Paragon Plus Environment

Page 13 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
A typical procedure for the synthesis of cyclohexyl(phenyl) methanone (3a): To a reaction
tube equipped with a magnetic stirring bar were added benzaldehyde (1a, 51 μL, 0.5 mmol),
TBP (380 μL, 2 mmol) and cyclohexane (2a, 10 mL). The tube was then flushed with nitrogen,
sealed and put into a glycerol bath inserted with an external sensor to measure the temperatures
during microwave heating in the cavity of a microwave synthesis apparatus. It was then
irradiated at 180 °C for 1 h. Upon completion, the resulting mixture was distillated under
reduced pressure to recover 2a for reuse. The residue was purified by column chromatography
on silica gel eluting with ethyl acetate/petroleum ether (1:100) to give cyclohexyl(phenyl)
methanone (3a). 3b-3ii were obtained in a similar manner.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
cyclohexyl(phenyl)methanone (3a)16: Eluent: ethyl acetate/petroleum ether (1:100); white solid
(54.5 mg, 58%); mp: 55-56 ºC; 1H NMR (400 MHz, CDCl3) δ: 1.27-1.56 (m, 5H), 1.74-1.77 (m,
1H), 1.84-1.92 (m, 4H), 3.28 (tt, J1 = 11.2 Hz, J2 = 3.2 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H),
13
7.54-7.58 (m, 1H), 7.95-7.97 (m, 2H). C NMR (100 MHz, CDCl3) δ: 25.9, 26.0, 29.4, 45.6,
128.3, 128.6, 132.7, 136.4, 203.9. MS: m/z 211 [MNa]+. HRMS (ESI-TOF) m/z calcd for
C13H16ONa [M+Na]+ 211.1093, found: 211.1084.
cyclohexyl(2-methoxyphenyl)methanone (3b)17: Eluent: ethyl acetate/petroleum ether (1:50);
1
yellowish liquid (67.6 mg, 62%); H NMR (400 MHz, CDCl3) δ: 1.22-1.44 (m, 5H), 1.66-1.70
(m, 1H), 1.78-1.82 (m, 2H), 1.89-1.93 (m, 2H), 3.19 (tt, J1 = 11.2 Hz, J2 = 3.2 Hz, 1H), 3.89 (s,
3H), 6.95 (d, J = 8.4 Hz, 1H), 6.99 (td, J1 = 7.6 Hz, J2 = 0.8 Hz, 1H), 7.40-7.45 (m, 1H), 7.50
(dd, J1 = 7.6 Hz, J2 = 1.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 26.0, 26.1, 28.8, 50.1, 55.6,
111.3, 120.7, 129.1, 129.8, 132.4, 157.6, 207.4. MS: m/z 241 [MNa]+.
(3-chlorophenyl)(cyclohexyl)methanone (3c)18: Eluent: ethyl acetate/petroleum ether (1:100);
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 25
1
2
3
4
5
6
7
8
9
yellowish liquid (45.5 mg, 41%); 1H NMR (400 MHz) δ: 1.29-1.55 (m, 5H), 1.74-1.78 (m, 1H),
1.85-1.91 (m, 4H), 3.21 (tt, J1 = 11.2 Hz, J2 = 3.2 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.54 (d, J =
7.6 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.91 (s, 1H). 13C NMR (100 MHz, CDCl3) δ: 25.8, 25.9,
29.3, 45.8, 126.3, 128.4, 129.9, 132.7, 135.0, 138.0, 202.7. MS: m/z 245 [MNa]+.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(3-bromophenyl)(cyclohexyl)methanone (3d)19: Eluent: ethyl acetate/petroleum ether (1:100);
1
yellowish liquid (55.9 mg, 42%); H NMR (400 MHz, CDCl3) δ: 1.27-1.52 (m, 5H), 1.74-1.77
(m, 1H), 1.85-1.90 (m, 4H), 3.21 (tt, J1 = 11.2 Hz, J2 = 3.2 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H),
7.69 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 8.07 (s, 1H). 13C NMR (100 MHz, CDCl3) δ:
25.8, 25.9, 29.3, 45.7, 123.0, 126.7, 130.2, 131.3, 135.6, 138.0, 202.5. MS: m/z 289 [MNa]+.
cyclohexyl(p-tolyl)methanone (3e)20: Eluent: ethyl acetate/petroleum ether (1:100); yellowish
1
solid (57.6 mg, 57%); mp: 62-63 ºC; H NMR (400 MHz, CDCl3) δ: 1.26-1.55 (m, 5H),
1.73-1.77 (m, 1H), 1.83-1.90 (m, 4H), 2.42 (s, 3H), 3.26 (tt, J1 = 11.2 Hz, J2 = 3.2 Hz, 1H), 7.27
13
(d, J = 7.2 Hz, 2H), 7.86 (d, J = 8.4 Hz, 2H). C NMR (100 MHz, CDCl3) δ: 21.6, 25.9, 26.0,
29.5, 45.5, 128.4, 129.3, 133.8, 143.6, 203.6. MS: m/z 225 [MNa]+.
cyclohexyl(4-methoxyphenyl)methanone (3f)21: Eluent: ethyl acetate/petroleum ether (1:50);
1
yellowish solid (71.9 mg, 66%); mp: 64-65 ºC; H NMR (400 MHz, CDCl3) δ: 1.26-1.56 (m,
5H), 1.73-1.76 (m, 1H), 1.83-1.89 (m, 4H), 3.23 (tt, J1 = 11.2 Hz, J2 = 3.2 Hz, 1H), 3.87 (s, 3H),
13
6.94 (dt, J1 = 8.8 Hz, J2 = 2.8 Hz, 2H), 7.95 (dt, J1 = 8.8 Hz, J2 = 2.8 Hz, 2H). C NMR (100
MHz, CDCl3) δ: 25.9, 26.0, 29.6, 45.3, 55.4, 113.7, 129.3, 130.5, 163.2, 202.5. MS: m/z 241
[MNa]+.
cyclohexyl(4-fluorophenyl)methanone (3g)20: Eluent: ethyl acetate/petroleum ether (1:100);
1
yellowish liquid (46.4 mg, 45%); H NMR (400 MHz, CDCl3) δ: 1.26-1.55 (m, 5H), 1.74-1.77
ACS Paragon Plus Environment

Page 15 of 25
The Journal of Organic Chemistry
1
2
3
4
(m, 1H), 1.85-1.90 (m, 4H), 3.19-3.26 (m, 1H), 7.14 (t, J = 8.8 Hz, 2H), 7.97-8.00 (m, 2H). 13C
5
6
7
2
3
NMR (100 MHz, CDCl3) δ: 25.8, 25.9, 29.4, 45.6, 115.7 (d, JC-F = 22.3 Hz), 130.9 (d, JC-F
=
8
9
8.7 Hz), 132.70 (d, 4JC-F = 2.4 Hz), 165.6 (d, 1JC-F = 252.5 Hz), 202.3. MS: m/z 229 [MNa]+.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(4-chlorophenyl)(cyclohexyl)methanone (3h)20: Eluent: ethyl acetate/petroleum ether (1:100);
1
yellowish solid (53.3 mg, 48%); mp: 62-63 ºC; H NMR (400 MHz, CDCl3) δ: 1.26-1.54 (m,
5H), 1.74-1.77 (m, 1H), 1.84-1.88 (m, 4H), 3.22 (tt, J1 = 11.2 Hz, J2 = 3.2 Hz, 1H), 7.44 (d, J =
13
8.4 Hz, 2H), 7.89 (d, J = 8.8 Hz, 2H). C NMR (100 MHz, CDCl3) δ: 25.8, 25.9, 29.4, 45.6,
128.9, 129.7, 134.7, 139.3, 202.6. MS: m/z 245 [MNa]+.
(4-bromophenyl)(cyclohexyl)methanone (3i)20: Eluent: ethyl acetate/petroleum ether (1:100);
1
yellowish solid (61.2 mg, 46%); mp: 77-78 ºC; H NMR (400 MHz, CDCl3) δ: 1.26-1.54 (m,
5H), 1.74-1.77 (m, 1H), 1.83-1.88 (m, 4H), 3.21 (tt, J1 = 11.2 Hz, J2 = 3.2 Hz, 1H), 7.61 (d, J =
13
8.8 Hz, 2H), 7.82 (d, J = 8.8 Hz, 2H). C NMR (100 MHz, CDCl3) δ: 25.8, 25.9, 29.3, 45.6,
127.9, 129.9, 131.9, 135.0, 202.9. MS: m/z 289 [MNa]+.
cyclohexyl(4-(trifluoromethyl)phenyl)methanone (3j)22: Eluent: ethyl acetate/petroleum ether
(1:100); yellowish liquid (46.1 mg, 36%); 1H NMR (400 MHz) δ: 1.27-1.56 (m, 5H), 1.75-1.78
(m, 1H), 1.85-1.92 (m, 4H), 3.23-3.29 (m, 1H), 7.74 (d, J = 8.0 Hz, 2H), 8.05 (d, J = 8.0 Hz,
2H). 13C NMR (100 MHz, CDCl3) δ: 25.7, 25.9, 29.2, 46.0, 123.7 (q, 1JC-F = 270.8 Hz), 125.7 (q,
3JC-F = 3.9 Hz), 128.6, 134.0 (q, 2JC-F = 32.6 Hz), 139.1, 202.9. MS: m/z 279 [MNa]+.
cyclohexyl(3,4-dimethoxyphenyl)methanone (3k)23: Eluent: ethyl acetate/petroleum ether
(1:50); yellowish solid (79.4 mg, 64%); mp: 47-48 ºC; 1H NMR (400 MHz, CDCl3) δ: 1.26-1.57
(m, 5H), 1.73-1.76 (m, 1H), 1.84-1.88 (m, 4H), 3.25 (tt, J1 = 11.2 Hz, J2 = 3.2 Hz, 1H), 3.95 (s,
3H), 3.96 (s, 3H), 6.90 (d, J = 8.0 Hz, 1H), 7.54 (s, 1H), 7.59 (dd, J1 = 8.4 Hz, J2 = 1.2 Hz, 1H).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 25
1
2
3
4
5
6
13C NMR (100 MHz, CDCl3) δ: 25.9, 26.0, 29.7, 45.2, 56.0, 56.1, 109.9, 110.6, 122.6, 129.6,
149.4, 153.0, 202.7. MS: m/z 271 [MNa]+.
7
8
9
cyclohexyl(2,4-dimethoxy-6-methylphenyl)methanone (3l): Eluent: ethyl acetate/petroleum
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
ether (1:50); yellowish solid (66.8 mg, 51%); mp: 61-62 ºC; H NMR (400 MHz, CDCl3) δ:
1.20-1.31(m, 3H), 1.35-1.44 (m, 2H), 1.66-1.68 (m, 1H), 1.77-1.80 (m, 2H), 1.88-1.91 (m, 2H),
2.20 (s, 3H), 2.84 (tt, J1 = 11.2 Hz, J2 = 3.2 Hz, 1H), 3.79 (s, 3H), 3.81 (s, 3H), 6.31 (s, 1H),
6.32 (s, 1H). 13C NMR (100 MHz, CDCl3) δ: 19.9, 25.9, 26.0, 28.3, 51.8, 55.3, 55.6, 96.0, 107.0,
124.3, 137.7, 158.1, 160.8, 210.8. HRMS (ESI-TOF) m/z calcd for C16H22O3Na [M+Na]+
285.1461, found: 285.1469.
cyclopentyl(phenyl)methanone (3m)16: Eluent: ethyl acetate/petroleum ether (1:100);
yellowish solid (48.7 mg, 56%); mp: 140-141 ºC; 1H NMR (400 MHz, CDCl3) δ: 1.64-1.78 (m,
4H), 1.91-1.96 (m, 4H), 3.74 (quint, J = 8.0 Hz, 1H), 7.46-7.50 (m, 2H), 7.54-7.58 (m, 1H),
7.98-8.00 (m, 2H). 13C NMR (100 MHz, CDCl3) δ: 26.3, 30.0, 46.4, 128.48, 128.52, 132.7,
136.9, 202.9. MS: m/z 197 [MNa]+.
cyclopentyl(2-methoxyphenyl)methanone (3n)19: Eluent: ethyl acetate/petroleum ether (1:50);
1
yellowish liquid (62.2 mg, 61%); H NMR (400 MHz, CDCl3) δ: 1.52-1.62 (m, 2H), 1.64-1.75
(m, 2H), 1.84-1.89 (m, 4H), 3.71 (quint, J = 8.0 Hz, 1H), 3.89 (s, 3H), 6.95 (d, J = 8.0 Hz, 1H),
6.99 (t, J = 7.6 Hz, 1H), 7.43 (td, J1 = 7.6 Hz, J2 = 1.6 Hz, 1H) , 7.55 (dd, J1 = 7.6 Hz, J2 = 1.6
Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 26.1, 29.6, 51.2, 55.6, 111.4, 120.6, 129.5, 129.9,
132.6, 157.8, 206.7. MS: m/z 227 [MNa]+.
cyclopentyl(p-tolyl)methanone (3o)24: Eluent: ethyl acetate/petroleum ether (1:100); yellowish
1
liquid (52.7 mg, 56%); H NMR (400 MHz, CDCl3) δ: 1.63-1.76 (m, 4H), 1.90-1.95 (m, 4H),
ACS Paragon Plus Environment

Page 17 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2.43 (s, 3H), 3.71 (quint, J = 8.0 Hz, 1H), 7.27 (d, J = 6.8 Hz, 2H), 7.90 (d, J = 8.0 Hz, 2H). 13C
NMR (100 MHz, CDCl3) δ: 21.5, 26.3, 30.0, 46.2, 128.6, 129.2, 134.5, 143.4, 202.5. MS: m/z
211 [MNa]+.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
cyclopentyl(4-methoxyphenyl)methanone (3p)24: Eluent: ethyl acetate/petroleum ether (1:50);
1
yellowish solid (62.3 mg, 63%); mp: 60-61 ºC; H NMR (400 MHz, CDCl3) δ: 1.62-1.70 (m,
2H), 1.72-1.78 (m, 2H), 1.89-1.94 (m, 4H), 3.68 (quint, J = 8.0 Hz, 1H), 3.88 (s, 3H), 6.95 (d, J
= 8.8 Hz, 2H), 7.98 (d, J = 8.8 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ: 26.3, 30.1, 46.0, 55.4,
113.6, 130.0, 130.7, 163.2, 201.5. MS: m/z 227 [MNa]+.
(3-chlorophenyl)(cyclopentyl)methanone (3q)25: Eluent: ethyl acetate/petroleum ether (1:100);
yellow liquid (40.6 mg, 39%); 1H NMR (400 MHz, CDCl3) δ: 1.65-1.76 (m, 4H), 1.90-1.96 (m,
4H), 3.67 (quint, J = 8.0 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.53 (dt, J1 = 8.0 Hz, J2 = 1.2 Hz, 1H),
13
7.86 (d, J = 8.0 Hz, 1H), 7.95 (t, J = 1.6 Hz, 1H). C NMR (100 MHz, CDCl3) δ: 26.3, 29.9,
46.5, 126.5, 128.6, 129.8, 132.7, 134.9, 138.5, 201.6. MS: m/z 231 [MNa]+.
(3-bromophenyl)(cyclopentyl)methanone (3r)19: Eluent: ethyl acetate/petroleum ether (1:100);
1
yellowish liquid (47.9 mg, 38%); H NMR (400 MHz, CDCl3) δ: 1.64-1.76 (m, 4H), 1.89-1.95
(m, 4H), 3.66 (quint, J = 8.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.68 (dt, J1 = 8.0 Hz, J2 = 1.2 Hz,
13
1H), 7.90 (d, J = 7.6 Hz, 1H), 8.10 (t, J = 1.6 Hz, 1H). C NMR (100 MHz, CDCl3) δ: 26.3,
29.9, 46.5, 122.9, 127.0, 130.1, 131.6, 135.6, 138.7, 201.4. MS: m/z 275 [MNa]+.
cyclopentyl(4-fluorophenyl)methanone (3s): Eluent: ethyl acetate/petroleum ether (1:100);
1
yellowish liquid (41.3 mg, 43%); H NMR (400 MHz, CDCl3) δ: 1.62-1.78 (m, 4H), 1.90-1.93
13
(m, 4H), 3.68 (quint, J = 8.0 Hz, 1H), 7.14 (t, J = 8.4 Hz, 2H), 8.00-8.03 (m, 2H). C NMR
2
3
(100 MHz, CDCl3) δ: 26.3, 30.0, 46.3, 115.6 (d, JC-F = 22.2 Hz), 131.1 (d, JC-F = 9.6 Hz),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 25
1
2
3
4
5
4
1
133.3 (d, JC-F = 3.6 Hz), 165.5 (d, JC-F = 252.5 Hz), 201.2. HRMS (ESI-TOF) m/z calcd for
6
7
C12H13FONa [M+Na]+ 215.0843, found: 215.0848.
8
9
(4-chlorophenyl)(cyclopentyl)methanone (3t)26: Eluent: ethyl acetate/petroleum ether (1:100);
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
yellowish liquid (45.8 mg, 44%); H NMR (400 MHz, CDCl3) δ: 1.62-1.78 (m, 4H), 1.91-1.95
13
(m, 4H), 3.67 (quint, J = 8.0 Hz, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 8.8 Hz, 2H). C
NMR (100 MHz, CDCl3) δ: 26.3, 29.9, 46.3, 128.8, 129.9, 135.2, 139.2, 201.6. MS: m/z 231
[MNa]+.
(4-bromophenyl)(cyclopentyl)methanone (3u)27: Eluent: ethyl acetate/petroleum ether (1:100);
1
yellowish liquid (55.4 mg, 44%); H NMR (400 MHz, CDCl3) δ: 1.65-1.76 (m, 4H), 1.89-1.95
13
(m, 4H), 3.67 (quint, J = 8.0 Hz, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.85 (d, J = 8.4 Hz, 2H). C
NMR (100 MHz, CDCl3) δ: 26.3, 29.9, 46.3, 127.8, 130.0, 131.8, 135.6, 201.7. MS: m/z 275
[MNa]+.
cyclopentyl(3,4-dimethoxyphenyl)methanone (3v)28: Eluent: ethyl acetate/petroleum ether
1
(1:50); yellowish liquid (72.6 mg, 62%); H NMR (400 MHz, CDCl3) δ: 1.65-1.74 (m, 4H),
1.89-1.94 (m, 4H), 3.69 (quint, J = 8.0 Hz, 1H), 3.94 (s, 3H), 3.95 (s, 3H), 6.90 (d, J = 8.0 Hz,
13
1H), 7.57 (s, 1H), 7.61 (d, J = 8.4 Hz, 1H). C NMR (100 MHz, CDCl3) δ: 26.3, 30.3, 45.9,
55.9, 56.0, 109.9, 110.6, 122.9, 130.1, 149.0, 153.0, 201.5. MS: m/z 257 [MNa]+.
cycloheptyl(phenyl)methanone (3w)29: Eluent: ethyl acetate/petroleum ether (1:100);
yellowish solid (47.5 mg, 47%); mp: 170-171 ºC; 1H NMR (400 MHz, CDCl3) δ: 1.55-1.73 (m,
8H), 1.79-1.84 (m, 2H), 1.92-1.97 (m, 2H), 3.42-3.49 (m, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.56 (t, J
= 7.6 Hz, 1H), 7.95 (d, J = 7.2 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ: 26.8, 28.3, 30.8, 46.6,
128.3, 128.6, 132.7, 136.5, 204.3. MS: m/z 225 [MNa]+.
ACS Paragon Plus Environment

Page 19 of 25
The Journal of Organic Chemistry
1
2
3
4
cycloheptyl(4-methoxyphenyl)methanone (3x)30: Eluent: ethyl acetate/petroleum ether (1:50);
5
6
7
1
yellowish liquid (61.5 mg, 53%); H NMR (400 MHz, CDCl3) δ: 1.53-1.72(m, 8H), 1.79-1.84
8
9
(m, 2H), 1.89-1.96 (m, 2H), 3.37-3.43 (m, 1H), 3.88 (s, 3H), 6.95 (dt, J1 = 9.6 Hz, J2 = 2.4 Hz,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
2H), 7.94 (dt, J1 = 9.6 Hz, J2 = 2.4 Hz, 2H). C NMR (100 MHz, CDCl3) δ: 26.9, 28.3, 31.0,
46.3, 55.5, 113.7, 129.3, 130.6, 163.2, 203.0. MS: m/z 255 [MNa]+.
(4-bromophenyl)(cycloheptyl)methanone (3y): Eluent: ethyl acetate/petroleum ether (1:100);
1
yellowish liquid (56.0 mg, 40%); H NMR (400 MHz, CDCl3) δ: 1.54-1.69 (m, 8H), 1.79-1.83
(m, 2H), 1.90-1.95 (m, 2H), 3.35-3.42 (m, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.80-7.82 (m, 2H). 13C
NMR (100 MHz, CDCl3) δ: 26.7, 28.3, 30.7, 46.6, 127.7, 129.9, 131.9, 135.1, 203.2. HRMS
(ESI-TOF) m/z calcd for C14H17BrONa [M+Na]+ 303.0355, found: 303.0359.
cyclooctyl(phenyl)methanone (3z)31: Eluent: ethyl acetate/petroleum ether (1:100); yellowish
1
liquid (54.0 mg, 50%); H NMR (400 MHz, CDCl3) δ: 1.60-1.70 (m, 8H), 1.75-1.81 (m, 4H),
1.85-1.92 (m, 2H), 3.47-3.53 (m, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.56 (t, J = 7.6 Hz, 1H), 7.95 (d,
13
J = 7.2 Hz, 2H). C NMR (100 MHz, CDCl3) δ: 25.5, 26.59, 26.61, 29.0, 44.9, 128.3, 128.6,
132.7, 136.5, 204.6. MS: m/z 239 [MNa]+.
cyclooctyl(4-methoxyphenyl)methanone (3aa)32: Eluent: ethyl acetate/petroleum ether (1:50);
1
yellowish liquid (71.4 mg, 58%); H NMR (400 MHz, CDCl3) δ: 1.56-1.69 (m, 8H), 1.74-1.89
(m, 6H), 3.42-3.48 (m, 1H), 3.88 (s, 3H), 6.95 (dt, J1 = 9.6 Hz, J2 = 2.4 Hz, 2H), 7.94 (dt, J1 =
13
9.6 Hz, J2 = 2.4 Hz, 2H). C NMR (100 MHz, CDCl3) δ: 25.6, 26.61, 26.63, 29.3, 44.5, 55.5,
113.7, 129.3, 130.6, 163.2, 203.2. MS: m/z 269 [MNa]+.
(4-bromophenyl)(cyclooctyl)methanone (3bb): Eluent: ethyl acetate/petroleum ether (1:100);
1
yellowish liquid (67.6 mg, 46%); H NMR (400 MHz, CDCl3) δ: 1.59-1.66 (m, 8H), 1.73-1.89
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 25
1
2
3
4
5
6
7
8
9
(m, 6H), 3.39-3.46 (m, 1H), 7.59-7.63 (m, 2H), 7.79-7.82 (m, 2H). 13C NMR (100 MHz, CDCl3)
δ: 25.4, 26.5, 26.6, 28.9, 45.0, 127.8, 129.9, 131.9, 135.2, 203.4. HRMS (ESI-TOF) m/z calcd
for C15H19BrONa [M+Na]+ 317.0511, found: 317.0528.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-ethyl-1-(4-methoxyphenyl)pentan-1-one (3cc), 2-ethyl-1-(4-methoxyphenyl)pentan-1-one
(3dd)33, and 1-(4-methoxyphenyl)heptan-1-one (3ee)34 were obtained from the reaction of 1f
with 2e as an unseperable mixture. The molar ratio of 3cc, 3dd and 3ee is 8:10:1, which was
determined by 1H NMR. Eluent: ethyl acetate/ petroleum ether (1:50); colorless liquid (66.0 mg,
1
60%). H NMR (400 MHz, CDCl3) δ: 0.85-0.89 (m, 4H), 1.17-1.19 (m, 1.5H), 1.24-1.31 (m,
3.5H), 1.42-1.58 (m, 1.5H), 1.72-1.81 (m, 1.5H), 2.91 (t, J = 7.6 Hz, 0.11H), 3.30-3.37 (m,
0.41H), 3.43 (sext, J = 6.8 Hz, 0.53H), 3.85-3.87 (m, 3H), 6.92-6.97 (m, 2H), 7.94-7.99 (m, 2H).
13C NMR (100 MHz, CDCl3) δ: 12.0, 14.0, 14.1, 14.3, 17.4, 20.8, 22.6, 22.8, 24.6, 25.6, 29.1,
29.7, 31.7, 33.7, 34.5, 38.3, 40.1, 47.0, 55.4, 113.66, 113.73, 113.74, 129.8, 130.3, 130.4, 130.5,
130.9, 163.30, 163.33, 203.2, 203.3. HRMS (ESI-TOF) m/z calcd for C14H20NaO2 [M+Na]+
243.1361, found: 243.1375.
cyclohexyl(2-hydroxyphenyl)methanone (3ff)35: Eluent: ethyl acetate/petroleum ether (1:50);
1
yellowish liquid (45.9 mg, 45%); H NMR (400 MHz, CDCl3) δ: 1.26-1.61 (m, 5H), 1.76-1.79
(m, 1H), 1.87-1.92 (m, 4H), 3.32 (tt, J1 = 11.6 Hz, J2 = 3.2 Hz, 1H), 6.91 (t, J = 7.6 Hz, 1H),
7.00 (d, J = 8.4 Hz, 1H), 7.46-7.50 (m, 1H), 7.80 (d, J = 7.6 Hz, 1H), 12.61 (s , 1H). 13C NMR
(100 MHz, CDCl3) δ: 25.78, 25.85, 29.6, 45.2, 118.3, 118.7, 118.9, 129.8, 136.3, 163.2, 210.2.
MS: m/z 227 [MNa]+.
(5-bromo-2-hydroxyphenyl)(cyclohexyl)methanone (3gg)36: Eluent: ethyl acetate/petroleum
1
ether (1:50); yellowish solid (60.6 mg, 43%); mp: 82-83 ºC; H NMR (400 MHz, CDCl3) δ:
ACS Paragon Plus Environment

Page 21 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1.24-1.63 (m, 5H), 1.77-1.80 (m, 1H), 1.88-1.91 (m, 4H), 3.21-3.26 (m, 1H), 6.91 (d, J = 8.8 Hz,
1H), 7.54 (d, J = 8.8 Hz, 1H), 7.87 (s, 1H), 12.53 (s , 1H). 13C NMR (100 MHz, CDCl3) δ: 25.6,
25.8, 29.5, 45.2, 110.4, 119.5, 120.8, 132.0, 138.8, 162.2, 209.3. MS: m/z 305 [MNa]+.
cyclopentyl(2-hydroxyphenyl)methanone (3hh)36: Eluent: ethyl acetate/petroleum ether (1:50);
yellowish liquid (38 mg, 40%); 1H NMR (400 MHz, CDCl3) δ: 1.67-1.80 (m, 4H), 1.94-1.99 (m,
4H), 3.77 (quint, J = 8.0 Hz, 1H), 6.90-6.94 (m, 1H), 7.00 (dd, J1 = 8.0 Hz, J2 = 1.2 Hz, 1H),
7.45-7.50 (m, 1H), 7.82 (dd, J1 = 8.0 Hz, J2 = 1.2 Hz, 1H), 12.56 (s, 1H). 13C NMR (100 MHz,
CDCl3) δ: 26.3, 30.3, 46.0, 118.5, 118.8, 119.1, 130.3, 136.0, 162.9, 209.3. MS: m/z 213
[MNa]+.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(5-bromo-2-hydroxyphenyl)(cyclopentyl)methanone (3ii)36: Eluent: ethyl acetate/petroleum
ether (1:50); yellowish liquid (54.9 mg, 41%); 1H NMR (400 MHz, CDCl3) δ: 1.71-1.77 (m, 4H),
1.94-1.97 (m, 4H), 3.69 (quint, J = 8.0 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 8.8 Hz,
1H), 7.90 (s, 1H), 12.46 (s, 1H). 13C NMR (100 MHz, CDCl3) δ: 26.3, 30.3, 46.0, 110.4, 120.2,
120.6, 132.4, 138.7, 162.0, 208.5. MS: m/z 290 [MNa]+.
ACKNOWLEDGMENTS
We are grateful to the National Natural Science Foundation of China (NSFC) (grant numbers
21272058, 21172057), Program for Innovative Research Team in Science and Technology in
University of Henan Province (15IRTSTHN003), Program for Science and Technology
Innovation Talents in Universities of Henan Province (15HASTIT005) for financial support.
1
Supporting Information. Mechanism studies, Copies of H and 13C NMR spectra. This
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 25
1
2
3
4
5
material is available free of charge via the Internet at http://pubs.acs.org.
6
7
8
REFERENCES
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(1) (a) Kim, J.-G.; Mishra, M. K.; Jang, D. O. Tetrahedron Lett. 2012, 53, 3527 and
references cited therein. (b) Sumino, S.; Ui, T.; Ryu, L. Org. Lett. 2013, 15, 3142. (c) Lee,
D.; Ryu, T.; Park, Y.; Lee, P. H. Org. Lett. 2014, 16, 1144. (d) Xie, L.; Wu, Y.; Yi, W.;
Zhu, L.; Xiang, J.; He, W. J. Org. Chem. 2013, 78, 9190. (e) Gu, L.; Jin, C.; Zhang, H.;
Zhang, L. J. Org. Chem. 2014, 79, 8453. (f) Du, P.; Li, H.; Wang, Y.; Cheng J.; Wan, X.
Org. Lett. 2014, 16, 6350 and references cited therein. (g) Zhao, M.-N.; Ran, L.; Chen, M.;
Ren, Z.-H.; Wang ,Y.-Y.; Guan, Z.-H. ACS Catal. 2015, 5, 1210.
(2) (a) Smith, M. B.; March, J. In March’s Advanced Organic Chemistry: Reactions,
Mechanisms, and Structure, 5th ed.; John Wiley & Sons: New York, 2001. (b) Veerasamy,
N.; Carlson, E. C.; Collett, N. D.; Saha, M.; Carter, R. G. J. Org. Chem. 2013, 78, 4779. (c)
Uto, Y.; Ogata, T.; Yohei, K.; Ueno, Y.; Miyazawa, Y.; Kurata, H.; Deguchi, T.;
Watanabe, N.; Konishi, M.; Okuyama, R.; Kurikawa, N.; Takagi, T.; Wakimoto, S.;
Ohsumi, J. Bioorg. Med. Chem. Lett. 2010, 20, 341.
(3) For recent examples on one-step synthesis of ketones from aldehydes, see: (a) Wu, Y.; Li,
B.; Mao, F.; Li, X.; Kwong, F. Y. Org. Lett. 2011, 13, 3258. (b) Schmidt, B.; Elizarov, N.;
Schilde, U.; Kelling, A. J. Org. Chem. 2015, 80, 4223.
(4) (a) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788. (b) Song,
G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651. (c) Chen, K.; Hu, F.; Zhang, S.-Q.;
Shi, B.-F. Chem. Sci. 2013, 4, 3906. (d) Zheng, C.; You, S.-L. RSC Adv. 2014, 4, 6173.
ACS Paragon Plus Environment

Page 23 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(5) (a) Zhang, S.-Y.; Zhang, F.-M.; Tu, Y.-Q. Chem. Soc. Rev. 2011, 40, 1937, and references
cited therein. (b) Roizen, J. L.; Harvey, M. E.; Du, B. J. Acc. Chem. Res. 2012, 45, 911,
and references cited therein. (c) Xie, J.; Pan, C. D.; Abdukadera, A.; Zhu, C.-J. Chem. Soc.
Rev. 2014, 43, 5245. and references cited therein.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(6) (a) Pitts, C. R.; Bloom, S.; Woltornist, R.; Auvenshine, D. J.; Ryzhkov, L. R.; Siegler, M.
A.; Lectka, T. J. Am. Chem. Soc. 2014, 136, 9780. (b) Sha, W. X.; Yu, J.-T.; Jiang, Y.;
Yang, H. T.; Cheng, J. Chem. Commun. 2014, 50, 9179. (c) Wang, L.; Sha, W. X.; Dai, Q.;
Feng, X. M.; Wu, W. T.; Peng, H. B.; Chen, B.; Cheng, J. Org. Lett. 2014, 16, 2088.
(7) Zhang, H.; Pan, C.; Jin, N.; Gu, Z.; Hu, H.; Zhu, C. Chem. Commun. 2015, 51, 1320.
(8) Zhu, Y.; Wei, Y. Chem. Sci. 2014, 5, 2379.
(9) Zhao, J.; Fang, H.; Qian, P.; Han, J.; Pan, Y. Org. Lett. 2014, 16, 5342.
(10) Zhao, J.; Fang, H.; Han, J.; Pan, Y. Org. Lett. 2014, 16, 2530.
(11) Guo, S.; Yuan, Y.; Xiang, J. New J. Chem. 2015, 39, 3093.
(12) McBurney, R. T.; Portela-Cubillo, F.; Walton, J. C. RSC Adv. 2012, 2, 1264.
(13) Zhang, Y.; Li, C.-J. Eur. J. Org. Chem. 2007, 4654.
(14) (a) Ghosh, A. K.; Osswald, H. L. Chem. Soc. Rev. 2014, 43, 6765. (b) Dillard, L. W.;
Yuan, J.; Leftheris, K.; Venkatraman, S.; Wu, G.; Jia, L.; Xu, Z.; Cacatian, S.;
Morales-Ramos, A.; Singh, S.; Zheng, Y. (Vitae Pharmaceuticals Inc.) WO 2011106414
A1, 1 Jan, 2011. (c) Cacatian, S.; Claremon, D. A.; Dillard, L. W.; Fuchs, K.; Heine, N.;
Jia, L.; Leftheris, K.; McKeever, B.; Morales-Ramos, A.; Singh, S.; Venkatraman, S.; Wu,
G.; Wu, Z.; Xu, Z.; Yuan, J.; Zheng, Y. (Vitae Pharmaceuticals Inc.) WO 2010105179 A2,
16 Sept, 2010.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 25
1
2
3
4
5
6
7
(15) (a) Bøgevig, A.; Federsel, H.-J.; Huerta, F.; Hutchings, M. G.; Kraut, H.; Langer, T.;
Lo w, P.; Oppawsky, C.; Rein, T.; Saller, H. Org. Process Res. Dev. 2015, 19, 357. (b)
8
9
Coe, J. W.; Bianco, K. E.; Boscoe, B. P.; Brooks, P. R.; Cox, E. D.; Vetelino, M. G. J. Org.
Chem. 2003, 68, 9964.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(16) Feng, Q.; Song, Q. L. J. Org. Chem. 2014, 79, 1867.
(17) Roche, M.; Hamze, A.; Provot, O.; Brion, J. D.; Alami, M. J. Org. Chem. 2013, 78, 445.
(18) Dar, D. E.; Thiruvazhi, M.; Abraham, P.; Kitayama, S.; Kopajtic, T. A.; Gamliel, A.;
Slusher, B. S.; Carroll, F. I.; Uhl, G. R. Eur. J. Med. Chem. 2005, 40, 1013.
(19) Qi, S.-B.; Li, M.; Li, S.; Zhou, J.-N.; Wu, J.-W.; Yu, F.; Zhang, X.-C.; Chan, A. S. C.; Wu,
J. Org. Biomol. Chem. 2013, 11, 929.
(20) Gutierrez-Bonet, A.; Flores-Gaspar, A.; Martin, R. J. Am. Chem. Soc. 2013, 135, 12576.
(21) Rao, M. L. N. Tetrahedron 2007, 63, 12917.
(22) Takemiya, A.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 14800.
(23) Niyazov, A. N. Izvestiya Akademii Nauk Turkmenskoi SSR, Seriya Fiziko-Tekhnicheskikh,
Khimicheskikhi Geologicheskikh Nauk 1978, 62.
(24) Roy, A. H.; Lenges, C. P.; Brookhart, M. J. Am. Chem. Soc. 2007, 129, 2082.
(25) Akhrem, I. S.; Churilova, I. M.; Orlinkov, A. V.; Afanas'eva, L. V.; Vitt, S. V.; Petrovskii,
P. V. Russian Chemical Bulletin (Translation of Izvestiya Akademii Nauk, Seriya
Khimicheskaya) 1998, 47, 918.
(26) Allwood, D. M.; Blakemore, D. C.; Ley, S. V. Org. Lett. 2014, 16, 3064.
(27) Rennison, D.; Conole, D.; Tingle, M. D.; Yang, J.; Eason, C. T.; Brimble, M. A. Bioorg.
Med. Chem. Lett. 2013, 23, 6629.
ACS Paragon Plus Environment

Page 25 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(28) Moffett, R. B.; Hanze, A. R.; Seay, P. H. J. Med. Chem. 1964, 7, 178.
(29) Gandeepan, P.; Parthasarathy, K.; Cheng, C.-H. J. Am. Chem. Soc. 2010, 132, 8569.
(30) Matzke, M.; Mohrs, K. H.; Raddatz, S.; Fruchtmann, R.; Hatzelmann, A.; Kohlsdorfer, C.;
Mueller-Peddinghau, R.; Theisen-Popp, P. Eur. Pat. Appl. 1993, EP 525571 A1
19930203.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(31) Starck, J.-P.; Provins, L.; Christophe, B.; Gillard, M.; Jadot, S.; Lo Brutto, P.; Quere, L.;
Talaga, P.; Guyaux, M. Bioorg. Med. Chem. Lett. 2008, 18, 2675.
(32) Taylor, H. M.; Jones, C. D.; Davenport, J. D.; Hirsch, K. S.; Kress, T. J.; Weaver, D. J.
Med. Chem. 1987, 30, 1359.
(33) Shen, D.; Poole, D. L.; Shotton, C. C.; Kornahrens, A. F.; Healy, M. P.; Donohoe, T. J.
Angew. Chem. Int. Ed. 2015, 54, 1642
(34) Parella, R.; Naveen; Kumar, A.; Babu, S. A. Tetrahedron Lett. 2013, 54, 1738
(35) Choy, P. Y.; Kwong, F. Y. Org. Lett. 2013, 15, 270.
(36) Yurchenko, N. N.; Niyazov, A. N.; Vakhabova, Kh. D.; Atlyev, Kh. A.; Khodzhaeva, V. L.;
Berezhnoi, V. G. Izvestiya Akademii Nauk Turkmenskoi SSR, Seriya Fiziko-
Tekhnicheskikh, Khimicheskikh i Geologicheskikh Nauk 1983, 74.
ACS Paragon Plus Environment