An investigation into the role of 2,6-lutidine as an additive for the RuCl3-NaIO4 mediated oxidative cleavage of olefins to ketones

Article abstract of DOI:10.1016/j.tetlet.2018.11.013

2,6-Lutidine has been identified as a beneficial additive for the oxidative cleavage of olefins to ketones by NaIO₄ in the presence of catalytic RuCl₃, improving the yield and shortening the reaction times. In the absence of 2,6-lutidine reactions stalled at the diol intermediate with incomplete conversion to the desired ketones. The reaction protocol described herein also avoids the use of harmful solvents such as CCl₄ and DCE and is tolerant of a range of functional groups.

Full text of DOI:10.1016/j.tetlet.2018.11.013

Accepted Manuscript
An investigation into the role of 2,6-lutidine as an additive for the RuCl3-
NaIO4 mediated oxidative cleavage of olefins to ketones
David W. Watson, Matthew Gill, Paul Kemmitt, Scott G. Lamont, Mihai V.
Popescu, Iain Simpson
PII:
S0040-4039(18)31329-7
https://doi.org/10.1016/j.tetlet.2018.11.013
TETL 50398
DOI:
Reference:
Tetrahedron Letters
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1 November 2018
5 November 2018
Please cite this article as: Watson, D.W., Gill, M., Kemmitt, P., Lamont, S.G., Popescu, M.V., Simpson, I., An
investigation into the role of 2,6-lutidine as an additive for the RuCl3-NaIO4 mediated oxidative cleavage of olefins
to ketones, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.11.013
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An investigation into the role of 2,6-lutidine as an additive for the RuCl3-NaIO4
mediated oxidative cleavage of olefins to ketones
David W. Watson*, Matthew Gill, Paul Kemmitt, Scott G. Lamont, Mihai V. Popescu and Iain Simpson
Medicinal Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK
ARTICLE INFO
ABSTRACT
Article history:
Received
2,6-Lutidine has been identified as a beneficial additive for the oxidative cleavage of olefins to
ketones by NaIO4 in the presence of catalytic RuCl3, improving the yield and shortening the
reaction times. In the absence of 2,6-lutidine reactions stalled at the diol intermediate with
incomplete conversion to the desired ketones. The reaction protocol described herein also avoids
the use of harmful solvents such as CCl4 and DCE and is tolerant of a range of functional
groups.
Received in revised form
Accepted
Available online
Keywords:
Alkene
2018 Elsevier Ltd. All rights reserved.
Oxidative Cleavage
Ketone
2,6-Lutidine
RuCl3 NaIO4
1. Introduction
Wishing to avoid oxidation conditions which employed
During a recent research programme, ketone 5 (Scheme 1)
was identified as a versatile intermediate which could be
accessed via the oxidative cleavage of alkene 3.
extremely toxic reagents (e.g. OsO4, Johnson-Lemieux2 oxidation
and Upjohn dihydroxylation3/diol cleavage protocols or ozone)
we investigated using the RuCl3-NaIO4 system. A disadvantage
of the widely used RuCl3-NaIO4 system, reported by Sharpless
and co-workers4 is that the solvent system CCl4:CH3CN:H2O
(2:2:3) requires hazardous solvents (CCl4 or DCE) for efficient
oxidative cleavage. We therefore sought oxidative conditions
using RuCl3-NaIO4 in the absence of CCl4 and DCE. Conditions
using RuCl3-NaIO4 in the absence of CCl4 and DCE existed in
the literature and in particular those reported by Yang and co-
workers5 initially appeared promising for the intended synthesis
of 5. In our hands the conditions of Yang and co-workers5 were
not efficient for substrate 3 (Table 1, entries 1 and 2), whereby
the reaction stalled at the diol intermediate 4, therefore a brief
optimisation was carried out (Table 1). The advantageous effect
of adding 2,6-lutidine to OsO4 catalysed oxidations is well
documented using both NaIO46 or PhI(OAc)2-NMO7 as oxidants,
however it had not been reported in conjunction with RuCl3
which led us to investigate the role of 2,6-lutidine in the RuCl3-
NaIO4 oxidative cleavage reaction.
b
a
1
2
3
c
2. Oxidation Optimisation
4
5
Scheme 1. Reagents and conditions: (a) t-butyl sulfonamide,
Sheppard’s reagent, THF, RT, 48 h, 100%; (b) 2-
(trimethylsilylmethyl)allyl acetate, Pd(PPh3)4 (10 mol%), THF, 40
oC, 2 h, 90%; (c) oxidative cleavage
Initially a range of solvent combinations were tested with
various equivalents of NaIO4 (Table 1, entries 1-2 and 4-5) which
all stalled at the diol intermediate 4. Pleasingly, a dramatic
increase in conversion and isolated yield of the desired ketone 5
was obtained when 2,6-lutidine was used as an additive (Table 1,
entry 7). Additionally, under these reaction conditions clean
conversion to the ketone was observed with intermediate diol 4
not detected by LCMS, suggesting that 2,6-lutidine enhances the
oxidative cleavage of the diol intermediate.
The route in Scheme 1 was appealing as a scalable synthesis to
alkene 3 had been developed via the cycloaddition1 of the
analogous sulfonyl imine 2.
*Corresponding author.
E-mail address: david.watson1@astrazeneca.com (D.W. Watson)

2
Tetrahedron Letters
Table 1. Optimisation of the oxidative cleavage to afford 5
RuCl3 (3.5 mol%)
Oxidant
Organic Solvent/H2O (1.5:1)
3
4
5
RT
Entry
Organic Solvent
Oxidant
Oxidant
(equiv.)
2
2,6-lutidine
(equiv.)
0
3:4:5 (%)a
Isolated
Yield 5 (%)
Not isolated
Time (h)
1
2
3
4
5
6
7
DCE
NaIO4
NaIO4
Oxonec
NaIO4
NaIO4
NaIO4
NaIO4
0:58:25
0:46:27c
0:58:25
0:58:25
0:45:17
21:0:66
0:0:87
1 h
DCE/CH3CN (1:1)
CH3CN
4b
0
0
0
0
2
2
23
16 h
16 h
1 h
4
Not isolated
Not isolated
Not isolated
Not isolated
86
CH3CN
2
CH3CN/CHCl3 (1:1)
CH3CN/CH2Cl2 (1:1)
CH3CN/CH2Cl2 (1:1)
3
1 h
3
1 h
4
1 h
aDetermined by LCMS analysis.
bNaIO4 (2 equiv.) afforded identical results to entry 1 and NaIO4 (6 equiv.) afforded 4 in 45% yield.
cNaHCO3 buffer (6 equiv.) added
additive, although in these cases the addition of 2,6-lutidine was
not detrimental to the reaction. Phenyl substitution on the alkene,
either directly or from the α position (34 and 38), was observed
to activate the substrate for the oxidative cleavage without 2,6-
lutidine after 60 minutes. However, a significant beneficial effect
to both conversion and isolated yield after 60 minutes was
observed when the activating phenyl was further removed from
the alkene as for examples 22 and 40. The reaction with 2,6-
lutidine is tolerant to acetal and ester functionality (substrates 24
and 26) and also pyridine substitution as shown by substrate 36,
although the isolated yield for the desired ketone 37 was modest.
3. Reaction Scope
The improved oxidation conditions were then investigated
using alternative 1-(tert-butylsulfonyl)-3-methylenepyrrolidine
substrates (Table 2) prepared via the analogous route used in
Scheme 1. The addition of 2,6-lutidine led to improved yields of
the oxidative cleavage product for a range of a range of pyrazole
protecting groups (Ts, PMB, Cbz) and the reaction conditions
were also effective using alternative aromatic groups such as
phenyl or thiophene. It is of note that the PMB protecting group
tolerates the strongly oxidizing RuCl3-NaIO4 conditions (Table
2, entry 2). The phenyl substituted analogue 8 displayed
incomplete conversion to the ketone after 1 hour without 2,6-
lutidine (Table 2, entry 3). Extended reaction times (18 h, Table
2 entry 4) also failed to fully convert alkene 8 to the desired
ketone highlighting the utility of 2,6-lutidine in this process.
The reaction scope was then investigated using less substituted
alkene 42 where over oxidation to the carboxylic acid was
possible (Scheme 2). In this situation the strong oxidative
conditions over oxidised alkene 42 to carboxylic acid 43, which
was observed as the major product of the reaction.
The scope of the reaction was investigated further by subjecting a
range of alkenes to the oxidation conditions with and without
2,6-lutidine (Table 3) to form the corresponding ketones. It can
be seen that a significant improvement in the yield of ketone 19
(38% to 71%) with 2,6-lutidine is observed with piperidine
analogue 18 and a similar effect is observed for close analogue
20. A general observation is that an improvement in yield is
observed after 1 hour with the 2,6-lutidine additive for less
activated substrates where the alkene is substituted from the α
and β positions only by alkyl groups, phenyl (from the β position
only) or Boc protected nitrogens (substrates 18, 20, 22, 26, 28
and 40). For substrate 30, (forming 31, an intermediate to form
vasopressin receptor V1a antagonists8) which has one electron
donating oxygen substituted from the α position, the reaction
progresses to completion after 1 hour without the need of the 2,6-
lutidine additive (Table 3, entry 8). There is however a beneficial
effect observed when the reaction is quenched after 10 minutes
instead of 60 minutes with the 2,6-lutidine additive. All reported
procedures for the synthesis of 31 utilise toxic OsO4, therefore
this protocol offers an improvement to the synthesis of
intermediate 31. Activated alkene substrates which contain two
electron donating oxygens substituted from either the γ or α
positions (24 and 32) were observed to completely convert to the
ketone after 10 minutes without the need for the 2,6-lutidine
a
43
42
44
Scheme 2. Reagents and conditions: (a) 2,6-lutidine (2 equiv.),
RuCl3 (3.5 mol%), NaIO4 (4 equiv.), CH3CN/CH2Cl2/H2O
1
(0.75:0.75:1), 1 h, RT, 100% crude recovery, H NMR indicates a
3:1 mixture of 43 (major) and 44 (minor)
4. Conclusion
A significant improvement to the oxidation of exocyclic
methylene compounds to their analogous ketones has been
developed using 2,6-lutidine for the first time as an additive (2
equivalents) in RuCl3-NaIO4 oxidations. This procedure avoids
the use of OsO4 and utilises more environmentally benign
solvents. Enhanced yields have been observed across a range of
substrates and is most prominent for substrates which do not
contain activating substituents. The addition of 2,6-lutidine for
activated alkenes to form ketones is not detrimental to the
reaction, however these conditions are not suitable for less
substituted alkenes where over oxidation to the carboxylic acid is
possible.
Table 2. Further examples of the oxidative cleavage of 1-(tert-butylsulfonyl)-3-methylenepyrrolidine substrates with and without
2,6-lutidine
Entry
Alkene
Ar
Intermediate
Ketone
Isolated Yield of Ketone (%)a
Time (h)

Tetrahedron Letters
diol
without 2,6-lutidine
with 2,6-lutidine
84 (0:0:1)
1
2
6
7
10
14
13 (0.2:4.1:1)
1
1
11
15
11 (2.5:0.5:1)
72 (0:0:1)
3
4
8
8
Ph
Ph
12
12
16
16
43 (0:1:1)
Not isolated (0:0.3:1)
80 (0:0:1)
Not performed
1
18
5
9
13
17
12 (5:3.3:0.2)
70 (0.05:0:1)
0.5
1
aThe ratio of alkene:diol:ketone (shown in brackets) are reported based on crude H-NMR prior to purification.
Table 3. Further examples of the oxidative cleavage of alkene substrates to ketones with and without 2,6-lutidinea
18 X = CH2; 19 X= O 20 X = CH2; 21 X= O 22 X = CH2; 23 X = O
24 X= CH2; 25 X = O 26 X = CH2; 27 X= O
28 X = CH2; 29 X = O
30 X = CH2; 31 X= O 32 X = CH2; 33 X= O 34 X = CH2; 35 X = O
36 X = CH2; 37 X = O
40 X= CH2; 41 X = O
38 X= CH2; 39 X = O
Entry
Alkene
Ketone
Isolated Yield of Ketone (%)
Conversion by 1H NMR shown in brackets
Time (min)
without 2,6-lutidine
38
with 2,6-lutidine
71
1
18
20
22
24
24
26
28
30
30
32
34
36
38
40
19
21
23
25
25
27
29
31
31
33
35
37
39
41
60
60
60
60
10
60
60
60
10
10
60
60
60
60
2
39 (69)
68 (100)
3
15 (17)
87 (100)
4
88 (100)
72 (100)
5
(100) Not isolated
10 (29)
Not performed
72 (100)
6
7
21 (20)
83 (100)
8
84 (100)
86 (100)
9
52 (61)
86 (100)
10
11
12
13
14
(100) Not isolated
43 (100)
Not performed
70 (100)
28 (100)
47 (100)
55 (100)
61 (100)
26 (36)
67 (100)
aReagents and conditions: RuCl3 (3.5 mol%), NaIO4 (4 equiv.), CH3CN:CH2Cl2:H2O (0.75:0.75:1.5), 2,6-lutidine (2 equiv. when added), RT, time as indicated in
Table 2.
6. Hua, Z.; Kang, Y.; Jin, Z; Mei, Y.; Yu, W., Org Lett, 2004, 6,
3217-3219.
References and notes
7. Adsool; V. A; Hale, C. R. H; Nicolaou, K. C., J Org Chem, 2010,
12, 1552-1555.
8. Bryans, J. S. et al.; Patent; 2004074291, 2004.
1. Jones, M. D.; Kemmitt, R. D. W., J Chem Soc, Chem Commun
1986, 1201.
2. Allen, D. S. Jr.; Johnson, W. S.; Lemieux, R. U; Pappo, R., J Org
Chem, 1956, 21, 478–479.
3. Cha, D. Y.; Kelly, R. C.; VanRheenen, V., Tetrahedron Lett,
1976, 17, 1973-1976.
Supplementary Material
4. Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B., J
Org Chem, 1981, 46, 3936-3938.
5. Yang, D.; Zhang, C., J Org Chem, 2001, 66, 4814-4818.
Supplementary data associated with this article can be found,
in the online version, at.

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An investigation into the role of 2,6-lutidine
as an additive for the RuCl3-NaIO4 mediated
oxidative cleavage of olefins to ketones
David W. Watson*, Matthew Gill, Paul Kemmitt, Scott G. Lamont, Mihai V. Popescu and Iain Simpson
R1
R1
RuCl3 (3.5 mol%), NaIO4 (4 equiv.),
O
R2
R2
2,6-lutidine (2 equiv.),
CH2Cl2, CH3CN, H2O, RT
Improved yields and shorter reaction times using 2,6-lutidine (2 equiv.) as an additive
2,6-Lutidine used as a beneficial additive for the
oxidation of olefins to ketones
The oxidative system uses NaIO4 in the presence of
catalytic RuCl3
Shortened reaction times and improved yields
observed
A range of functional groups are tolerated