Improved synthesis of 2-norbornanone

Article abstract of DOI:10.1007/s11164-015-2213-0

Herein a two-step process for the synthesis of 2-norbornanone with 91 % overall yield has been developed. The addition of sublimation inhibitors suppressed the sublimation of norbornene in the process of sulfuric acid-promoted hydration and increased the yield of 2-norbornanol significantly under mild conditions. Additionally, reuse of sulfuric acid has been achieved. A 4-hydroxy-TEMPO/CuCl/TBN triple-component catalyst system for the highly selective aerobic oxidation of 2-norbornanol was developed and displayed high atom efficiency and yield.

Full text of DOI:10.1007/s11164-015-2213-0

Res Chem Intermed
DOI 10.1007/s11164-015-2213-0
Improved synthesis of 2-norbornanone
Heng Zhang1,2 Shuixiang Fu1,2 Ming Tao3
•
•
•
Zutai Liao3 Chao Qian1,2 Xinzhi Chen1,2
•
•
Received: 11 May 2015 / Accepted: 6 August 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract Herein a two-step process for the synthesis of 2-norbornanone with 91 %
overall yield has been developed. The addition of sublimation inhibitors suppressed
the sublimation of norbornene in the process of sulfuric acid-promoted hydration and
increased the yield of 2-norbornanol significantly under mild conditions. Additionally,
reuse of sulfuric acid has been achieved. A 4-hydroxy-TEMPO/CuCl/TBN triple-
component catalyst system for the highly selective aerobic oxidation of 2-norbornanol
was developed and displayed high atom efficiency and yield.
Keywords Norbornene Á Sublimation inhibitors Á Catalytic oxidation Á
4-Hydroxy-TEMPO Á 2-Norbornanone
Introduction
2-Norbornanone is a widely used intermediate in the synthesis of various biocyclo
derivatives and has been attracting much research interest [1, 2]. One-step aerobic
oxidation of norbornene to 2-norbornanone has been achieved. Dzhemileva [3]
provided a method of aerobic oxidation of norbornene to 2-norbornanone, catalyzed
by expensive palladium chloride and copper chloride. Starokon [4] achieved an
approximately 11 % yield of 2-norbornanone by oxidation of norbornene with
&
Heng Zhang
zhanghengmhp@163.com
Xinzhi Chen
xzchen@zju.edu.cn
1
2
College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China
Key Laboratory of Biomass Chemical Engineering of Ministry of Education,
Zhejiang University, Hangzhou, China
3
Jiangxi Renming Pharmaceutical Chemicals Ltd., Jiujiang, China
123

H. Zhang et al.
nitrous oxide. By far, the routine utilising norbornene as a starting material through
the intermediate 2-norbornanol is still being widely developed. The hydroboration
of norbornene, followed by oxidative workup provides exo-2-norborneol in
excellent yields and with stereoselectivity [5–7]. Hydration of norbornene also
occupies a particular place in industry and laboratory practice. Acids [8], zeolites
[9], and transition-metal complexes [10] are used as hydration catalysts. Khusnut-
dinov [10] achieved a 90 % yield in the presence of chromium and copper
complexes, limited by the requirement for carbon tetrachloride as a co-
reactant/solvent.
Acid catalytic hydration of norbornene has been studied in the past. Herman [8]
provided a method for the preparation of exo-2-norborneol and dinorbornyl, ether
by the use of aqueous 25- to 50 % sulfuric acid, whereby a 50 % yield of
2-norborneol was obtained. Norbornene is easy to sublimate. In order to avoid the
sublimation of norbornene and obtain a high yield, hydration reactions generally
were performed under low temperature or in high pressure systems. Elderfield [11]
reported a method of sulfuric acid-catalyzing hydration of norbornene with 85 %
sulfuric acid in 0 °C and achieved only a 50 % yield. Ozen [12] achieved a 95 %
yield though via an hydration reaction between norbornene and subcritical water
under tough conditions of 120 °C and 4 MPa. During our work, we found that the
introduction of some volatile organics (named sublimation inhibitors) could achieve
a high yield of 2-norbornanol under higher temperature and normal pressure.
In the process of catalytic oxidation of 2-norbornanol, oxygen, chromium
compounds and sodium hypochlorite have been used as oxidants. Goff [13]
achieved a 100 % yield using pyridinium chlorochromate (PCC) for oxidants. Toxic
PCC in stoichiometric amounts causes severe environmental problems and low
utilization of reactant atoms. Stevens [14] achieved a 92 % yield of 2-norbornanone
by the use of considerable aqueous sodium hypochlorite. Therefore, economical and
environmental oxidants have been developed. To date, numerous transition-metal-
catalyzed aerobic oxidations of alcohols have been developed, such as palladium
[15, 16], gold [17] and ruthenium [18]. Besides, Uyanik [19] found that the catalytic
system consisting of HBr/NaNO2 was effective for the aerobic oxidation of
alcohols. In addition, Espenson [20] achieved a 95 % yield of 2-norbornanone with
hydrogen peroxide with methyltrioxorhenium and bromide ions as co-catalysts.
The stable tetraalkylnitroxyl radical TEMPO (2,2,6,6-tetramethylpiperidine-1-
oxyl) is a well-known oxidation catalyst, which is widely used in organic synthesis.
Of particular synthetic interest is the oxidation of alcohols to carbonyl compounds
[21, 22]. Industry generally employs nitroxyl derivatives functionalized in the 4
position, such as 4-hydroxy-TEMPO obtained from the cheap precursor triace-
toneamine, a readily available chemical manufactured in large amounts as a light
stabilizer for plastics. 4-Hydroxy-TEMPO generally is applied in small quantities
(0.1–10 mol%); clearly it must be recovered from homogeneous reaction mixtures
and separated from the product. Tert-butyl nitrite (TBN) generally serves as an
efficient NO equivalent to activate molecular oxygen and enabled the aerobic
oxidation at very high-volume efficiency.
In this paper, we developed a two-step process for the synthesis of 2-norbor-
nanone (Scheme 1). Easy sublimation of norbornene was solved by introducing
123

Improved synthesis of 2-norbornanone
sublimation inhibitors to the hydration process and achieved a 96 % yield of exo-2-
norborneol under mild conditions. The sulfuric acid was reused after the reaction. A
4-hydroxy-TEMPO/CuCl/TBN triple-component catalyst system for selective
aerobic oxidation of 2-norbornanol was developed and a 95 % yield of 2-norbor-
nanone was achieved.
Experimental
2-Norbornanol
10.0 g (0.106 mol) of norbornene was added to a solution of 150 g of 33 % H2SO4
and 10 mL of dichloromethane (sublimation inhibitor). The mixture was heated at
80 °C for 4 h with continuous stirring. Then, the solution was extracted with
dichloromethane. The dichloromethane extract was washed with saturated sodium
bicarbonate solution and evaporated in vacuum to constant weight; 11.4 g of white
solid was obtained with a melting point (m.p.) of 149.2–149.9 °C (lit [23]:
149–150 °C). In this process, no formation of the endo-2-norborneol was found.
Raffinate (sulfuric acid solution) can be reused by adding H2O equimolar amounts
of norbornene consumed.
2-Norbornanol: Proton nuclear magnetic resonance (1H NMR; 400 MHz,
deuterated chloroform (CDCl3)): d = 3.76 (d, J = 6.5 Hz, 1H), 2.25 (s, 1H), 2.14
(d, J = 3.4 Hz, 1H), 1.66 (ddd, J = 13.0, 6.8, 2.1 Hz, 1H), 1.62–1.53 (m, 2H),
1.52–1.34 (m, 2H), 1.29 (d, J = 13.0 Hz, 1H), 1.12 (dd, J = 9.8, 1.0 Hz, 1H),
1.08–0.88 (m, 2H). Carbon 13 NMR (13C NMR; 100 MHz, CDCl3): d = 74.9, 44.3,
42.3, 35.4, 34.4, 28.1, 24.4.
2-Norbornanone
11.5 g of 2-norbornanol, 0.346 g (0.002 mol) of 4-OH-TEMPO, 0.412 g (0.004 mol)
of TBN and 0.05 g (0.0005 mol) of CuCl were added to 50 mL of dichloromethane.
The mixture was charged in a high-pressure reactor keeping the oxygen pressure at
0.4 MPa. The mixture was heated at 80 °C for 2 h with continuous stirring. Then the
CuCl (0.03 g) was filtered. The solvent was evaporated in vacuum, and the filtrate was
separated to a layer of TBN (0.39 g) and a layer of product. The product layer was
steam distilled and the fraction between 98 and 100 °C was collected; 10.7 g of white
solid with a m.p. of 91.0–91.8 °C (lit [24]: 91–92 °C) was obtained. The mixture after
steam distillation was extracted with dichloromethane and 0.35 g of 4-hydroxy-
TEMPO was recycled.
Scheme 1 Two-step synthesis of 2-norbornanone
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H. Zhang et al.
1
2-Norbornanone: H NMR (400 MHz, CDCl3): d = 2.67 (s, 1H), 2.59 (s, 1H),
2.06 (dd, J = 17.8, 2.8 Hz, 1H), 1.95–1.65 (m, 4H), 1.66–1.49 (m, 2H), 1.44 (dd,
J = 9.3, 7.2 Hz, 1H). 13C NMR (100 MHz, CDCl3): d = 218.2, 49.8, 45.2, 37.7,
35.3, 27.2, 24.2.
Results and discussion
Sulfuric acid-catalyzing hydration of norbornene
During our work, experiment without sublimation inhibitors achieved only a 60.2 %
yield in 24 h (entry 1, Table 1). We found that norbornene was easy to sublimate
under the reaction temperature; then, sublimated nonbornene condensed rapidly and
attached to the condenser pipe. To solve this problem, sublimation inhibitors were
introduced to the reaction system. The amount of sublimation inhibitors whose
boiling points were below the reaction temperature ensured the gaseous phase
partial pressure of the sublimation inhibitor was large enough to reduce the partial
pressure of norbornene and, consequently, suppress sublimation. Besides, the
sublimation inhibitors showed good solubility for norbornene and circulation of
evaporation–condensation could wash down the sublimated nonbornene attached to
the condenser pipe.
Experiments with sublimation inhibitors achieved a 94.5 % yield in 4 h (entry 2,
Table 1). Different sublimation inhibitors were introduced to the reaction system
and results are listed in Table 1. Parallel experiments found that dichloromethane at
Table 1 Results of norbornene hydration with different sublimation inhibitors and dosages
Entry
Sublimation
inhibitor
B.p (oC)
Reaction
time (h)
Conversion
(%)
Yield
(%)
1
None
/
24
4
67.6
99.4
97.9
99.1
98.1
98.8
99.5
94.7
98.2
99.6
60.2
94.5
92.4
93.5
91.4
92.5
94.3
88.8
92.1
90.1
2a
3b
4c
5a
6a
7a
8a
9a
10a
Dichloromethane
Dichloromethane
Dichloromethane
n-Hexane
39.8
39.8
39.8
86.2
80.7
36.0
83.5
40*80
78.4
11
5
7
Cyclohexane
n-Pentane
5
4
1,2-Dichloroethane
Petroleum ether
Ethanol
6
5
3
Reaction conditions: 33 % H2SO4, 80 °C, 4.8:1 mol ratio of sulfuric acid to norbornene, mechanical
stirring
a
Sublimation inhibitors/norbornene = 1 mL/g
b
Sublimation inhibitors/norbornene = 0.5 mL/g
c
Sublimation inhibitors/norbornene = 2.5 mL/g
123

Improved synthesis of 2-norbornanone
a dosage of 1 mL/g of norbornene gave a better result. However, excessive
sublimation inhibitor in the liquid phase extracted norbornene from the sulfuric
acid, resulting in deficient contact between the reactant and catalyst; as such, the
yield and reaction rate declined.
Reaction temperature and sulfuric acid concentration also had appreciable
impacts on the direct hydration of norbornene, as shown in Table 2. High
temperature and sulfuric acid concentration accelerated the reaction rate, which,
meanwhile, increased the by-product dinorbornyl ether; 80 °C and a 33 % sulfuric
acid concentration showed better results (entry 5, Table 2). Moreover, the sulfuric
acid can be reused by adding quantitative H2O for five times without any significant
loss in catalyst activity (entry 7, Table 2).
Aerobic oxidation of 2-norbornol
The radical 4-hydroxy-TEMPO is utilised in a variety of industrial applications as a
highly selective oxidation catalyst, and the oxidation mechanism of TEMPO has
been proposed [22]. Based on previous work, we proposed the bielectronic
oxidation mechanism of 4-hydroxy-TEMPO oxidation of 2-norbornol (Scheme 2).
However, we found that using 4-hydroxy-TEMPO alone gave a poor yield of
2-norbornanone (entry 1, Table 3). Semmelhack [25] and He [26] provided two-
component catalyst systems (TEMPO/CuCl and TEMPO/TBN). Besides, Hoover
[27] discussed the mechanism of copper(I)/TEMPO-catalyzed aerobic alcohol
oxidation.
During our work, however, experiments with 4-hydroxy-TEMPO/CuCl and
4-hydroxy-TEMPO/TBN showed low yields of 2-norbornanone (entry 5, 8,
Table 3). Inspired by previous work, a 4-hydroxy-TEMPO/CuCl/TBN triple-
component catalyst system was developed and achieved highly selective aerocic
oxidation of 2-norbornanol (entry 3, Table 3).
Table 2 Results of norbornene hydration under different conditions
Entry
Sulfuric acid
concentration (%)
Temperature
(°C)
Reaction
time (h)
Conversion
(%)
Yield
(%)
1a
2a
3a
4b
5c
6a
7a
95
33
25
33
33
33
33
80
80
80
80
80
55
95
0.5
4.0
8
98.7
99.1
98.3
99.6
99.5
99.1
99.3
21.2
94.5
93.0
93.9
94.3
93.9
89.6
4
4
14
3
Reaction conditions:1 mL/g ratio of dichloromethane to norbornene, 4.8 molar ratio of sulfuric acid to
norbornene, mechanical stirring
a
Recycle times of sulfuric acid was 0
b
Recycle times of sulfuric acid was 3
c
Recycle times of sulfuric acid was 5
123

H. Zhang et al.
Scheme 2 Bielectronic oxidation mechanism of 4-OH-TEMPO oxidations
Table 3 Results of 2-norbornanol oxidation with different catalyst compositions
Entry
4-Hydroxy-TEMPO
(mol%)
TBN
(mol%)
CuCl
(mol%)
Conversion
(%)
Yield
(%)
1
4
0
4
4
4
0
3
5
4
4
4
4
0
0
0
2
1.5
2
0.5
0.5
0.5
0.5
0.5
0.5
0
87.7
100
100
0
81.4
92.9
93.0
0
3
4a
3
5
2
6
2
76.2
100
45.2
74.1
100
100
70.1
93
7
2
8
2
39.2
77.9
93.3
92.3
9
2
0.2
1
10
11b
2
2
0.5
Reaction conditions: 80 °C; 0.4 MPa; ratio of dichloromethane to 2-norbornanol was 500 mL/mol;
reaction time was 2 h
a
Reaction time was 1.5 h
b
Recycled 4-hydroxy-TEMPO, TBN and CuCl were added into the fresh catalysts and the overall
composition remained unchanged
Scheme 3 Proposed mechanism for 4-hydroxy-TEMPO/CuCl/TBN-catalyzed aerobic oxidation of
alcohols
Furthermore, we proposed a possible mechanism of the 4-hydroxy-TEMPO/CuCl/
TBN triple-component catalyst system for aerobic oxidation of alcohols (Scheme 3).
Oxoammonium cation, which is initially oxidized from 4-OH-TEMPO, is an active
123

Improved synthesis of 2-norbornanone
Table 4 Results of 2-norbornanol oxidation under different conditions
Entry
Solvent
Temperature
(°C)
Oxygen
pressure (MPa)
Conversion
(%)
Yield
(%)
1a
2a
3a
4a
5a
6a
7b
8b
9b
10b
11b
Dichloromethane
1,2-Dichloroethane
Toluene
80
80
80
80
80
80
55
80
90
80
80
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.2
0.5
100
92.9
92.2
10.2
14.6
77.2
69.9
6.5
100
15.7
22.5
84.9
77.8
9.2
Chlorobenzene
Acetonitrile
Acetic acid
Dichloromethane
Dichloromethane
Dichloromethane
Dichloromethane
Dichloromethane
57.5
63.1
29.2
61.1
50.6
56.8
23.5
55.1
Dosage of solvent: 500 mL/mol (2-norbornanol); 4-hydroxy-TEMPO: 2 mol%; TBN:4 mol%; CuCl:
0.5 mol%
a
Reaction time was 2 h
b
Reaction time was 1 h
oxidant of alcohols in this system. The running of cycle I continuously provides the
oxoammonium cation by oxidizing 4-OH-TEMPOH, the reduced form of 4-OH-
TEMPO, with Cu2?, and the latter is reduced into Cu?. The reoxidation of Cu? to Cu2?
by NO2 is illustrated as cycle II, which is the key for a catalytic amount of Cu2? in the
oxidation system. NO2 is reduced to NO when it completes the oxidation of Cu?. Under
hightemperatures, TBN can release NO because of its thermal instability. The oxidation
of NO into NO2 is a process easily accomplished with molecular oxygen (cycle III), and
the coupling of the three cycles furnishes an efficient aerobic oxidation system.
The influence 4-hydroxy-TEMPO, TBN and CuCl dosages was also investigated.
2 mol% of 4-hydroxy-TEMPO, 4 mol% of TBN and 0.5 mol% of CuCl constituted
optimum catalyst dosages (entry 3, Table 3). Moreover, 4-OH-TEMPO, TBN and
CuCl can be partially recycled and reused without any significant loss in catalyst
activity (entry 11, Table 3).
Solvents had a powerful influence on the oxidation of 2-norbornanol, and
dichloromethane matched the system best (entry 1, Table 4). Wiht oxygen pressure
and temperature increasing, the reaction rate and yield of the product increased
rapidly and then remained stable. Then, 80 °C and 0.4 MPa were chosen.
Conclusion
In conclusion, a high-efficiency, economic and environmental synthesis of
2-norbornanone from norbornene has been developed. Importantly, the addition
of a sublimation inhibitor increased the yield of 2-norbornanol significantly, and the
principles of sublimation inhibitors have been discussed. Reuse of sulfuric acid was
also achieved. A recoverable and efficient 4-hydroxy-TEMPO/CuCl/TBN triple-
123

H. Zhang et al.
component catalyst system for the highly selective aerobic oxidation of 2-norbor-
nanol was developed; the system displayed high atom efficiency. Furthermore, the
catalytic oxidation mechanism was proposed.
Acknowledgments The authors are grateful for the financial support from the Natural Science
Foundation of China (21376213, 21476194) and the Zhejiang Provincial Public Technology Research of
China (2014C31123).
References
1. P.V.R. Schleyer, D.C. Kleinfelter, Org. Synth. 42, 79 (1962)
2. N.L. Reddy, J. Hill, L. Ye, P.B. Fernandes, D.M. Stout, Bioorg. Med. Chem. Lett. 14, 22 (2004)
3. G. Dzhemileva, V. Odinokov, U. Dzhemilev, Bull. Acad. Sci. USSR Div. Chem. Sci. 36, 1 (1987)
4. E. Starokon, K. Dubkov, D. Babushkin, V. Parmon, G. Panov, Adv. Synth. Catal. 346, 2–3 (2004)
5. N. Satyanarayana, M. Periasamy, Tetrahedron Lett. 25, 23 (1984)
6. H.C. Brown, V. Somayaji, S. Narasimhan, J. Org. Chem. 49, 25 (1984)
7. D. Albanese, D. Landini, A. Maia, M. Penso, Synlett 2000, 07 (2000)
8. H.A. Bruson, US 2345573 (1944)
ˇ
9. M. Kucera, M. Kralik, M. Mat’as, P. Hudec, M. Hronec, Collect. Czechoslov. Chem. Commun. 60, 3
´
ˇ
(1995)
10. R. Khusnutdinov, T. Oshnyakova, N. Shchadneva, Russ. J. Org. Chem. 49, 10 (2013)
11. R.C. Elderfield, E.T. Losin, J. Org. Chem. 26, 6 (1961)
12. R. Ozen, N.S. Kus, J. Serb. Chem. Soc. 72, 10 (2007)
13. D. Goff, J. Zhang, C. Sylvain, WO2008083356A1 (2008)
14. R.V. Stevens, K.T. Chapman, H.N. Weller, J. Org. Chem. 45, 10 (1980)
15. S. Higashibayashi, A. Masud Reza, H. Sakurai, J. Org. Chem. 75, 13 (2010)
16. X. Ye, M.D. Johnson, T. Diao, M.H. Yates, S.S. Stahl, Green Chem. 12, 7 (2010)
17. T. Mitsudome, A. Noujima, T. Mizugaki, K. Jitsukawa, K. Kaneda, Adv. Synth. Catal. 351, 11–12
(2009)
18. S. Venkatesan, A.S. Kumar, J.-M. Zen, Tetrahedron Lett. 49, 28 (2008)
19. M. Uyanik, R. Fukatsu, K. Ishihara, Chem. Asian J. 5, 3 (2010)
20. J.H. Espenson, Z. Zhu, T.H. Zauche, J. Org. Chem. 64, 4 (1999)
21. K. Chabita, P. Mandal, H. Mahal, T. Mukherjee, Res. Chem. Intermed. 27, 6 (2001)
22. R. Ciriminna, M. Pagliaro, Org. Process Res. Dev. 14, 1 (2009)
´
23. G. Komppa, in IX Congreso Internacional de Quımica Pura y Aplicada, vol. 4 (1934), pp. 321–322
24. K. Buchner, J. Meis, DE 951867 (1956)
25. M. Semmelhack, C.R. Schmid, D.A. Cortes, C.S. Chou, J. Am. Chem. Soc. 106, 11 (1984)
26. X. He, Z. Shen, W. Mo, N. Sun, B. Hu, X. Hu, Adv. Synth. Catal. 351, 1–2 (2009)
27. J.M. Hoover, B.L. Ryland, S.S. Stahl, J. Am. Chem. Soc. 135, 6 (2013)
123