One-pot formal dehydrogenative ketone synthesis from aldehydes and non-activated hydrocarbons

Article abstract of DOI:10.1248/cpb.c20-00075

Ketones are a fundamental functionality found throughout a range of natural and synthetic compounds, making their synthesis essential throughout the chemical disciplines. Herein, we describe a one-pot synthesis of ketones via decatungstate-mediated formal dehydrogenative coupling between aldehydes and non-activated hydrocarbons. A variety of substituted benzaldehydes and cycloalkanes could be used in the optimized reaction to produce the desired ketones in moderate yields. The decatungstate photocatalyst functions in two reactions in this synthesis, catalyzing both the coupling and oxidation steps of the process. Notably, the reaction displays both high atom economy and sustainability, as it uses light and oxygen as key energy sources.

Full text of DOI:10.1248/cpb.c20-00075

Chemical and Pharmaceutical Bulletin Advance Publication by J-STAGE
DOI:10.1248/cpb.c20-00075
Advance Publication
February 19, 2020
Chem. Pharm. Bull.
(Communication to the Editor)
One-Pot Formal Dehydrogenative Ketone Synthesis from Aldehydes
and Non-Activated Hydrocarbons
Kenzo Yahata,*,a Shin Yoshioka,a Shuhei Hori,a Shu Sakurai,a Yuki Kaneko,a Kai Hasegawa,a
and Shuji Akaia
aGraduate School of Pharmaceutical Sciences, Osaka University; 1-6 Yamada-oka, Suita,
Osaka 565-0871, Japan.
* Correspondence e-mail: yahata-k@phs.osaka-u.ac.jp
Tel/fax: 06-6879-8210
Ⓒ 2020 The Pharmaceutical Society of Japan

Summary
Ketones are a fundamental functionality found throughout a range of natural and
synthetic compounds, making their synthesis essential throughout the chemical disciplines.
Herein, we describe a one-pot synthesis of ketones via decatungstate-mediated formal
dehydrogenative coupling between aldehydes and non-activated hydrocarbons. A variety of
substituted benzaldehydes and cycloalkanes could be used in the optimized reaction to
produce the desired ketones in moderate yields. The decatungstate photocatalyst functions
in two reactions in this synthesis, catalyzing both the coupling and oxidation steps of the
process. Notably, the reaction displays both high atom economy and sustainability, as it
uses light and oxygen as key energy sources.
Keywords
photo catalysis, ketone synthesis, C-H activation, one-pot reaction
Chemical and Pharmaceutical Bulletin Advance Publication

Introduction
Ketones are among the most fundamental functional groups in organic chemistry
and are constituents of a wide range of organic molecules. Although various routes for
ketone synthesis have been reported, most require relatively expensive starting materials,
such as organic halides and organometallic reagents.1-19) We recently reported the coupling
of aldehydes and non-activated hydrocarbons using CrCl3 (3 eq.)20) and
tetrabutylammonium decatungstate (TBADT; 10 mol%) (Chart 1a).21-41) During this work,
a small quantity of ketone 4 was observed in the crude mixture. Side product 4 is likely
produced through oxidation of the primary product alcohol 3 by TBADT and
contaminating oxygen (Fig. 1).42-44) Notably, this reaction was promoted by UV light and
oxygen, which are clean and sustainable energy sources. Moreover, the overall
transformation occurred via highly atom-economic cross-dehydrogenative coupling45)
between aldehydes and non-activated hydrocarbons nominally. We therefore sought to
promote the oxidation of alcohols into ketones in a single flask.
Herein, we describe a novel, one-pot formal dehydrogenative synthesis of ketones
from aryl aldehydes and non-activated hydrocarbons (Chart 1b). This reaction proceeds via
TBADT-mediated C-H activation and oxidation using oxygen as the terminal oxidant.
Results and Discussion
The reaction conditions were optimized using benzaldehyde (1a) and
cyclohexane (2a) (Table 1). The initial coupling step was performed using our previously
optimized conditions: CrCl3 (3 eq.), TBADT (10 mol%), Cs2CO3 (1.5 eq.), N2 atmosphere,
and 390 nm irradiation (Chart 1).21) Following completion of the coupling reaction, the
system was opened and a balloon filled with dry air was attached. The reaction was then
continued for an additional 24 h to provide the desired ketone 4a in 21% yield, along with
the unreacted coupling product alcohol 3a in 35% yield (entry 2). We then changed the dry
air to an oxygen balloon, which increased the yield of 4a to 49% (entry 3). Decreasing the
reaction time (12 h) for the second oxidation decreased the yield of 4a to 39% (entry 4).
When the second oxidation step was performed without UV light, the yield of 4a decreased
dramatically (7%) (entry 5), resembling the yield of 4a (5%) obtained when only the first
oxidation step was performed (entry 1). From this work, we concluded that the second
treatment of the crude coupling product under an oxygen atmosphere with UV irradiation
Chemical and Pharmaceutical Bulletin Advance Publication

for 24 h completed the conversion of alcohol 3a into ketone 4a and that both oxygen and
UV are essential for the transformation.
Having established the optimized conditions, we next investigated the scope of the
reaction (Table 2). Various aldehydes 1 could be employed in the reaction with cyclohexane,
although the yields of the corresponding ketones 4 were moderate (19-49%) (entries 1-8).
Substituted benzaldehydes bearing a range of functionalities, including bromo, methoxy,
and ester groups, were well-tolerated under the reaction conditions to give the desired
ketones 4c-4e in 33-48% yield (entries 3-6), similar to that of the unsubstituted 4a (49%)
(entry 1). For the substrate bearing a t-butyldimethylsilyl (TBS)-oxy group, the non-TBS
protected ketone was obtained in 15% yield along with the desired product 4h (19%)
(entry 8). Other cycloalkanes, including cyclopentane (2b), cyclooctane (2c), and
norbornane (2d), could also function as coupling partners in this reaction (entries 9-11).
Unfortunately, more attractive nucleophile precursors, such as N,N-dimethylacetoamide
(DMA) and anisole, did not afford the desired ketones 4, although their corresponding
alcohols 3 were isolated in 72 and 40% yield, respectively (entries 12 and 13).
Conclusion
We have developed a one-pot formal dehydrogenative coupling between hydrocarbons and
aldehydes. Although the yields are moderate, this route displays several advantages over
traditional ketone syntheses: (1) non-activated hydrocarbons are commercially available
and pre-functionalization is not required; (2) the reaction is atom-economical; (3) the same
photocatalyst, TBADT, functions in both stages of the reaction, i.e., the
hydrocarbon/aldehyde coupling and oxidation of the resulting alcohol to the ketone; and (4)
the ketone-forming step requires only the addition of O2 and light, which are green and
sustainable energies. Studies focused on increasing the yield and substrate scope of this
novel reaction are currently underway in our research group.
• Acknowledgments
This work was supported in part by a JSPS Grant-in-Aid for Young Scientists (Grant
Number: JP18K14868), the Teijin Pharma Award in Synthetic Organic Chemistry Japan, a
Grant-in-Aid from the Tokyo Biochemical Research Foundation, the Keihanshin
Consortium for Fostering the Next Generation of Global Leaders in Research
Chemical and Pharmaceutical Bulletin Advance Publication

(K-CONNEX), established by Building of Consortia for the Development of Human
Resources in Science and Technology, MEXT, and the Platform Project for Supporting
Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug
Discovery and Life Science Research (BINDS)) from AMED (Grant Number:
JP19am0101084).
• Conflict of Interest
The authors declare no conflict of interest.
• Supplementary Materials
The online version of this article contains supplementary materials.
Chemical and Pharmaceutical Bulletin Advance Publication

• References and Notes
1) Onaka M., Matsuoka Y., Mukaiyama T., Chem. Lett., 10, 531 (1981)
2) Oçafrain M., Devaud M., Troupel M., Perichon, J., J. Chem. Soc. Chem. Commun.,
2331 (1995)
3) Dolhem E., Oçafrain M., Nédélec J. Y., Troupel M., Tetrahedron, 53, 17089 (1995)
4) Oçafrain M., Devaud M., Nédélec J. Y., Troupel M., J. Organomet. Chem., 560, 103
(1998)
5) Oçafrain M., Dolhem E., Nédélec J. Y., Troupel M., J. Organomet. Chem., 571, 37
(1998)
6) Tokuyama H., Yokoshima S., Yamashita T., Fukuyama T., Tetrahedron Lett., 39, 3189
(1998)
7) Dolhem E., Barhdadi R., Folest J., Nédélec J. Y., Troupel M., Tetrahedron, 57, 525
(2001)
8) Wotal A. C., Weix D. J., Org. Lett., 14, 1476 (2012)
9) Yin H., Zhao C., You H., Lin K., Chem. Commun., 48, 7034 (2012)
10) Cherney A. H., Kadunce N. T., Reisman S. E., J. Am. Chem. Soc., 135, 7442 (2013)
11) Wotal A. C., Ribson R. D., Weix D. J., Organometallics, 33, 5874 (2014)
12) Zhang X., Wang Z., Fan X., Wang J., J. Org. Chem., 80 10660 (2015)
13) Joe C. L., Doyle A. G., Angew. Chem. Int. Ed. 55, 4040 (2016)
14) Ai Y., Ye N., Wang Q., Yahata K., Kishi Y., Angew. Chem. Int. Ed. 56, 10791 (2017)
15) Amani J., Molander G. A. Org. Lett., 19, 3612 (2017)
16) Kumar V. P., Babu V. S., Yahata K., Kishi Y., Org. Lett., 19, 2766 (2017)
17) Ackerman L. K. G., Martinez Alvarado J. I., Doyle A. G., J. Am. Chem. Soc. 140,
14059 (2018)
18) Shi R., Hu X., Angew. Chem. Int. Ed. 58, 7454 (2019)
19) Wang J., Cary B. P., Bayer P. D., Gellman S. H., Weix D. J., Angew. Chem. Int. Ed., 58,
12081 (2019)
20) Although the reaction requires an excess amount of CrCl3, chromium salts are low toxic
in the +2 and +3 oxidation states; oral-rat LD 50 for Cr2O3 > 2700 mg/kg.
Chromium(III) and its Inorganic Compounds., The MAK-Collection for Occupational
Health and Safety. DOI: 10.1002/3527600418.mb1606583vee4614 (2014)
Chemical and Pharmaceutical Bulletin Advance Publication

21) Yahata K., Sakurai S., Hori S., Yoshioka S., Kaneko Y., Hasegawa K., Akai S., Org.
Lett., 10.1021/acs.orglett.0c00096 (2020)
22) For examples of TBADT-mediated C-H activation reactions (see also Ref. 23-41).
Dondi D., Cardarelli A. M., Fagnoni M, Albini A., Tetrahedron, 62, 5527 (2006)
23) Dondi D., Fagnoni M., Albini A., Chem. Eur. J., 12, 4153 (2006)
24) Ravelli D., Zema M., Mella M., Fagnoni M., Albini A., Org. Biomol. Chem., 8, 4158
(2010)
25) Ravelli D., Albini A., Fagnoni M., Chem. Eur. J., 17, 572 (2011)
26) Ravelli D., Montanaro S., Zema M., Fagnoni M., Albini A., Adv. Synth. Catal., 353,
3295 (2011)
27) Ryu I., Tani A., Fukuyama T., Ravelli D., Fagnoni M., Albini A., Angew. Chem. Int. Ed.,
50, 1869 (2011)
28) Montanaro S., Ravelli D., Merli D., Fagnoni M., Albini A., Org. Lett., 14, 4218 (2012)
29) Ryu I., Tani A., Fukuyama T., Ravelli D., Montanaro S., Fagnoni M., Org. Lett., 15,
2554 (2013)
30) Helperin S. D., Fan H., Chang S., Martin R. E., Britton R., Angew. Chem. Int. Ed., 53,
4690 (2014)
31) Okada M., Fukuyama T., Yamada K., Ryu I., Ravelli D., Fagnoni M., Chem. Sci., 5,
2893 (2014)
32) Bonassi F., Ravelli D., Protti S., Fagnoni M., Adv. Synth. Catal., 357, 3687 (2015)
33) West J. G., Huang D., Sorensen E., Nat. Commun., 6, 10093 (2015)
34) Murphy J. J., Bastida D., Paria S., Fagnoni M., Melchiorre P., Nature, 532 218 (2016)
35) Quattrini M. C., Fujii S Yamada K., Fukuyama T., Ravelli D., Fagnoni M., Ryu I.,
Chem. Commun., 53, 2335 (2017)
36) Fukuyama T., Nishikawa T., Yamada K., Ravelli D., Fagnoni M., Ryu I., Org. Lett., 19,
6436 (2017)
37) Fukuyama T., Yamada K., Nishikawa T., Ravelli D., Fagnoni M., Ryu I., Chem. Lett.,
47, 207 (2018)
38) Ravelli D., Fagnoni M., Fukuyama T., Nishikawa T., Ryu I., ACS Catal. 8, 701 (2018)
39) Perry I. B., Brewer T. F., Sarver P. J., Schultz D. M., DiRocco D. A., MacMillan D. W.
C., Nature, 560, 70 (2018)
Chemical and Pharmaceutical Bulletin Advance Publication

40) Yuan Z., Yang H., Malik N., Čolvić M., Weber D. S., Wilson D., Bénard F., Martin R.
E., Warren J. J., Schaffer P., Britton R., ACS Catal., 9, 8276 (2019)
41) Fukuyama T., Nishikawa T., Ryu I., Eur. J. Org. Chem., DOI: 10.1002/ejoc.201901135
(2019)
42) Tzirakis M. D. Lykakis I. N., Orfanopoulos M., Chem. Soc. Rev., 38, 2609 (2009)
43) Symeonidis T. S., Tamiolakis I., Armatas G. S., Lykakis I. N., Photochem. Photobiol.
Sci., 14, 563 (2015)
44) Laudadio G., Govaerts S., Wang Y., Ravelli D., Koolman H. F., Fagnoni M., Djuric S.
W., Noël T., Angew. Chem. Int. Ed. 57, 4078 (2018)
45) Li C.-J., Acc. Chem. Res., 42, 335-344 (2009)
Chemical and Pharmaceutical Bulletin Advance Publication

Table 1. Optimization of one-pot ketone synthesisa)
Entry Oxidation Conditions Yieldb)
1c)
-
5%
2
dry air balloon
O2 balloon
O2 balloon
O2 balloon
21%
49%
39%
7%
3
4d)
5e)
a) Reaction conditions: 1a (0.20 mmol, 1 eq.), 2a (30 eq.), CrCl3 (3 eq.), TBADT (10
mol%), Cs2CO3 (1.5 eq.), MeCN/EtOAc (1:1, 0.1 M), 40 W 390 nm Kessil lamp, fan, 48 h
for each entry. Then, O2 source, 40 W 390 nm Kessil lamp, fan, 24 h unless otherwise
noted. b) All yields are of 4a isolated by SiO2 chromatography. c) Reaction was stopped
after the first step, and no second oxidation step was conducted. d) The second oxidation
step was stopped after 12 h. e) The second oxidation step was conducted in dark.
Chemical and Pharmaceutical Bulletin Advance Publication

Table 2. Substrate scope of one-pot ketone synthesisa)
CrCl3 (3 eq.)
TBADT (10 mol%)
Cs2CO3 (1.5 eq.)
MeCN/EtOAc (1:1, 0.1 M), 48 h
40W 390 nm Kessil lamp, fan, N2
O
H
O
+
R
R
H
then
O
2 balloon, 12 h
1
2
40W 390 nm Kessil lamp
4
Entry 1
2
4
Yieldb)
49%
1
1a
2a
4a
2
2a
20%
48%
33%
37%
45%
23%
19%
24%
31%
32%
1b
4b
4c
3
2a
1c
CHO
4
2a
MeO
1d
4d
O
5
2a
1e
MeO2C
4e
6
2a
1f
4f
7
2a
1g
4g
8
2a
1h
4h
9c)
10c)
11
1a
1a
1a
2b
4i
2c
4j
2d
4k
12d)
13d)
1a
1a
0%
0%
DMA
anisole
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a) Reaction conditions: 1a (0.20 mmol, 1 eq.), 2a (30 eq.), CrCl3 (3 eq.), TBADT (10
mol%), Cs2CO3 (1.5 eq.), MeCN/EtOAc (1:1, 0.1 M), 40 W 390 nm Kessil lamp, fan, 48 h,
then O2 balloon, 40 W 390 nm Kessil lamp, fan, 24 h. b) All yields are of isolated 4. c) 2
(20 eq.) was used. d) 2 was used as a cosolvent: 1 (0.80 mmol), Cs2CO3 (1.5 eq.), CrCl3 (3
eq.), TBADT (10 mol%), MeCN/EtOAc/2 (2:1:3, 0.067 M), two 40 W 390 nm Kessil
lamps, fan, 48 h. then O2 balloon, two 40 W 390 nm Kessil lamps, fan, 24 h.
Chemical and Pharmaceutical Bulletin Advance Publication

(a) Previous Work
CrCl3 (3 eq.)
TBADT (10 mol%)
Cs2CO3 (1.5 eq.)
OH
3
O
4
O
+
R1
R1
+
R1
H
MeCN/EtOAc
N2, h
1
2a
major product
~5%
4[(Nn-Bu4)+]
(b) This Work
CrCl3 (3 eq.)
TBADT (10 mol%)
Cs2CO3 (1.5 eq.)
MeCN/EtOAc
N2, h
O
O
4-
W
W
O
O
O
O
O
W
O
O
O
O
O
O
O
W
O
O
W
O
O
W O
O
O
O
O
W
O
O
W
O
O
O
+
O
R1
O
O
R1
H
O
then
O2
MeCN/EtOAc, h
W
O
W
O
1
2a
4
TBADT
major product
Chart 1. (a) Coupling Reaction between Aldehydes and Non-Activated Hydrocarbons.
(b) One-pot Formal Dehydrogenative Ketone Synthesis.
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Fig. 1. Reaction Mechanism
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