One-pot oxidative cleavage of olefins to synthesize carboxylic acids by a telescoped ozonolysis-oxidation process

Article abstract of DOI:10.1055/s-0035-1560659

A mild one-pot ozonolysis-oxidation process of alkenes to synthesize carboxylic acids is described. Conducting the ozonolysis in an aqueous organic solvent eliminates secondary ozonide formation and the intermediates generated are readily converted into a carboxylic acid by adding sodium chlorite. Following a reductive quench, the desired acids are isolated in high purity and high yield by simple extraction.

Full text of DOI:10.1055/s-0035-1560659

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2016, 27, 245–248
letter
245
B. M. Cochran
Letter
Synlett
One-Pot Oxidative Cleavage of Olefins to Synthesize Carboxylic
Acids by a Telescoped Ozonolysis–Oxidation Process
Brian M. Cochran*
OH
H
simple
O3
O
Synthetic Technologies, Process Development, Amgen, Inc.,
One Amgen Center Drive, Thousand Oaks, CA 91320, USA
cochranb@amgen.com
extraction
– H2O2
+ H2O2
+ H2O
R
R
OH
H
OH
i. NaClO2
R
R
O
ii. NaHSO3
OH
R
O
10% H2O–MeCN
0 °C
H
OH
– H2O
9 examples
R = aryl, alkyl
59–98% yield
scalable!
Received: 28.07.2015
Accepted after revision: 15.09.2015
Published online: 13.10.2015
In the widely accepted mechanism (Scheme 1), ozone
reacts with an alkene by a 1,3-dipolar addition to generate
the primary ozonide 2 which rapidly undergoes a retrocy-
clization to a mixture of carbonyl and carbonyl oxide inter-
mediates 3.7 These intermediates quickly recombine in
aprotic solvents to form the secondary ozonide 4 which is
subsequently reduced to aldehydes, ketones, or alcohols. In
the past decade, a number of techniques have been devel-
oped to address the potential hazards of ozonolysis reac-
tions,8 namely managing the formation of high-energy in-
termediates and the control of the exothermic nature of the
reaction. Of utmost concern, secondary ozonides 4 have a
high energy of decomposition and yet, they often react
slowly by reaction workup.9 The combination of high ener-
gy and slow reactivity gives way to their explosive nature.10
One method to minimize the accumulation of these inter-
mediates and increase the safety of the process is by run-
ning the ozonolysis in a continuous manner.11
DOI: 10.1055/s-0035-1560659; Art ID: st-2015-r0586-l
Abstract A mild one-pot ozonolysis–oxidation process of alkenes to
synthesize carboxylic acids is described. Conducting the ozonolysis in
an aqueous organic solvent eliminates secondary ozonide formation
and the intermediates generated are readily converted into a carboxylic
acid by adding sodium chlorite. Following a reductive quench, the de-
sired acids are isolated in high purity and high yield by simple ex-
traction.
Key words ozonolysis, carboxylic acids, green chemistry, alkenes, oxi-
dation
The oxidative cleavage of olefins by ozone is an efficient
and environmentally sustainable method to generate oxy-
genated compounds.1 Olefin ozonolysis is commonly used
to prepare aldehydes, ketones, and alcohols through forma-
tion of a secondary ozonide followed by an in situ degrada-
tion with a reducing agent.2 A direct conversion of olefins to
esters by an ozonolysis has also been studied.3 When the fi-
nal target is a carboxylic acid, a two-step process is em-
ployed where, after reduction of the ozonide, the isolated
aldehyde is oxidized in a separate step.4 In other instances,
the carboxylic acid can be generated post ozonolysis by the
addition of hydrogen peroxide; however, only a limited
number of procedures document this process.5 An alterna-
tive to ozone, metal-catalyzed oxidative cleavage of olefins
with stoichiometric oxidant, also generate carboxylic acids
in a one-pot procedure.6 Unfortunately, these catalysts are
often costly and are difficult to remove which is further ex-
acerbated when used as the final synthetic step of an active
pharmaceutical ingredient (API). As part of our design of an
efficient and scalable process to an API, we sought a metal-
free, one-pot ozonolysis–oxidation reaction of an olefin to
synthesize carboxylic acids.
O
H
O
H
R
H
H
O3/O2
O
R
H
R
R
H
O
H
CH2Cl2
–78 °C
or
1
4
OH
O
–O
O
O
O
O
+
H
H
H/R
H
+
H/R
H
R
H
3
2
Scheme 1 Ozonolyis reaction pathway in aprotic solvents
Additives and solvent choice in the ozonolysis reaction
have been used to avoid secondary ozonide formation. The
addition of protic solvents, such as methanol (Scheme 2, eq.
1), result in the formation of methyl peroxy acetals 5 in lieu
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 245–248

246
B. M. Cochran
Letter
Synlett
of the secondary ozonide by intercepting intermediate 3.
The methyl peroxy acetals are typically reduced to the cor-
responding carbonyl or alcohol but in some instances, they
can be isolated.12 Catalytic pyridine also suppresses ozonide
formation at cryogenic temperatures, and the aldehyde can
be isolated without a reductive workup (Scheme 2, eq. 2).13
By conducting an ozonolysis reaction in an aqueous/organic
solvent mixture (Scheme 2, eq. 3), Dussault found the alde-
hyde product could be isolated without a reductive quench
by way of a hydroperoxy acetal intermediate 6. In addition,
the ozonolysis could be conducted at 0 °C instead of using
cryogenic conditions (Scheme 2, eq. 3).14 We conceived an
ozonolysis method in which, utilizing an aqueous solvent,
the short-lived intermediate 6 formed at noncryogenic
temperatures could be intercepted with a second oxidant to
form a carboxylic acid in one pot.
had a pH value of ca. 1. This drop in pH was not solely due
to the ozonolysis of the substrate as a decrease of the pH
value was measured when a 10% water–acetonitrile solu-
tion was ozonolyzed in the absence of an alkene.22
OH
H
O
– H2O2
R
OH
H
O2/O3, 0 °C
+ H2O2
R
O
+ H2O
10% H2O–MeCN
OH
H
– H2O
R
OH
7
8
R = PhCH2CH2–
Scheme 3 Ozonolysis reaction mixture in 10% H2O–MeCN
The observation that the end of reaction was acidic in-
formed our selection of sodium chlorite as a second oxi-
dant. Sodium chlorite acts as a mild oxidizing agent in
aqueous media at a pH < 4 converting aldehydes into car-
boxylic acids (Pinnick oxidation).23 Given the high concen-
tration of aldehyde in equilibrium with the other ozolysis
products, the mixture should all convert into the carboxylic
acid in the presence of sodium chlorite. Though the Pinnick
oxidation is traditionally carried out in THF–t-BuOH sol-
vents with a phosphate buffer and a hypochlorite scaven-
ger, acetonitrile and hydrogen peroxide have been success-
fully used as solvent and scavenger, respectively.24
A 2 M sodium chlorite solution was added to the ozono-
lysis end-of-reaction solution in one equivalent, increments
monitoring for carboxylic acid formation (Table 1). Gratify-
ingly, after the first equivalent was added and aged for one
hour, acid 9 was produced in 34%. Slow delivery of the chlo-
rite solution to the reaction mixture was required to control
the exothermicity of the oxidation reaction. A second
equivalent of sodium chlorite was added, aged, and the
mixture further converted into acid 9, however, the reac-
tion appeared to stall at 60%. A third equivalent of sodium
chlorite appeared to have little impact after aging for an
hour; however,25 aging the reaction overnight following ad-
dition of a fourth equivalent of sodium chlorite resulted in
the full conversion into carboxylic acid 9. The excess
amount of oxidant required is most likely due to the chlo-
rite decomposition in the presence of reaction byprod-
ucts.26
HO
O
MeOH
(1)
H
R
–50 °C
OMe
5
–O
O
O
pyridine
O
+
(2)
(3)
CH2Cl2
–78 °C
H/R
H
+
H
H
R
H/R
H
3
HO
H
O
H2O
0 °C
O
OH
– H2O2
R
R
6
Scheme 2 Ozonolysis conditions which avoid secondary ozonide for-
mation
We began by replicating the ozonolysis conditions de-
veloped by Dussault using 4-phenylbutene (7) in 10 vol-
umes of 5% water–acetonitrile at 0 °C.15 Ozone was deliv-
ered to the reaction with a subsurface sparger while sweep-
ing the reactor headspace with nitrogen.16 In addition to an
ice bath, the exothermicity of the reaction was controlled
by the rate of ozone delivery. Diluting the reaction from 10
volumes to 20 volumes of solvent also permitted the heat to
dissipate more readily.17 In the 5% aqueous system a small
quantity of the secondary ozonide (2 area%) was formed;
however, no evidence for the secondary ozonide was found
upon increasing the solvent water content to 10% (<1
area%).18 In lieu of using a chemical indicator to determine
the ozonolysis reaction endpoint,19 the head space of the
reactor was monitored for ozone.20
Prior to isolation of acid 9, a reductive workup was nec-
essary to safely quench any residual oxidants such as chlo-
rite, hypochlorite, and hydrogen peroxide. The reaction was
quenched with a 2 M sodium bisulfite solution; a mildly
exothermic reaction. The temperature rise was controlled
by the addition rate. The reaction mixture remained yellow
until approx 3.5 equivalents of the solution was added. A
total of four equivalents of sodium bisulfite was required
before the reaction mixture tested negative for oxidants. Af-
Once the ozonolysis was complete, the reaction compo-
sition was analyzed to help determine a plausible method
to produce the desired carboxylic acid in situ (Scheme 3). A
mixture of aldehyde, peroxyacetal, and hydrate intermedi-
ates 8 were observed to be in equilibrium21 and the solution
tested positive for peroxides. Unexpectedly, the solution
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 245–248

247
B. M. Cochran
Letter
Synlett
Table 1 Ozonolysis End-of-Reaction Solution Reacting with Sodium
Table 2 Substrate Scope of the Telescoped Ozonolysis–Oxidation Pro-
Chlorite
cess
OH
H
i. O3, 10% H2O–MeCN
ii. 2 M NaClO2 (4 equiv)
iii. 2 M NaHSO3 (4 equiv)
O
HO
O
OH
– H2O2
+ H2O2
+ H2O
R
R
R
OH
H
R
O
2 M NaClO2
R
O
OH
Entry
1
Substrate
Product, yield (%)a
OH
H
OH
– H2O
9
8
O
R = PhCH2CH2-
96
83
NaClO2 (equiv)
Tint rise (°C)
Time aged (h)
9 (area%)
OH
1
2
3
4
12
8
1
1
34
60
O
2
3
4
1
67
1
16
100
OH
O
ter a simple extraction, 3-phenylpropanoic acid 9 was iso-
lated in 96% yield and >95% purity by 1H NMR.
MeO
MeO
84
With the data collected from these experiments, a gen-
eral one-pot ozonolysis–oxidation procedure was devel-
oped to synthesize carboxylic acids. In a typical experiment
the primary alkene in 20 volumes of 10% water–acetonitrile
is subjected to ozone at 0 °C. Once ozone is detected in the
reaction head space, the ozonolysis is stopped. An aqueous
solution of sodium chlorite (2 M, 4 equiv) is added to the
reaction at a rate adequate to maintain the internal reaction
temperature <15 °C, and the reaction is stirred at ambient
temperatures for >12 hours. The end-of-reaction mixture is
quenched with sodium bisulfite (2 M, 4 equiv) at a rate such
that the internal temperature is <35 °C. Following quench,
the product is isolated by extraction.27
The generality of this process was evaluated with a vari-
ety of primary alkenes (Table 2). Benzoic acids with either
electron-rich or electron-poor substituents were readily
synthesized from the corresponding styrenes (Table 2, en-
tries 2–4). 4-Vinylpyridine was an adequate substrate pro-
viding isonicotinic acid albeit in moderate yield (Table 2,
entry 5). Unfunctionalized and acetylated monoalkylal-
kenes (Table 2, entries 6 and 7) were smoothly transformed
into their corresponding carboxylic acids as well as the un-
protected alcohol in 7-octene-1-ol (Table 2, entry 8). N-Al-
lyl benzamide (Table 2, entry 9) was converted into the cor-
responding acid using these conditions which exemplifies a
new method to generate amino acids.
OH
O
4
5
Cl
Cl
84
OH
O
N
N
59b
OH
Me
6
7
8
Me
O
7
7
91
OH
AcO
7
AcO
O
7
91
OH
HO
HO
O
5
5
98
OH
H
H
O
N
O
N
9
O
Ph
Ph
In summary, a mild, one-pot, and metal-free process to
oxidatively cleave alkenes to carboxylic acids has been de-
veloped. By utilizing an ozonolysis in aqueous solvent, the
olefin is cleaved, thereby avoiding high-energy intermedi-
ates under noncryogenic conditions. These intermediates
are further oxidized with sodium chlorite to produce the
desired carboxylic acid. Because this process contains no
87
a Isolated yields.
b Assay yield.
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248
B. M. Cochran
Letter
Synlett
heavy metals, pure products are isolated by a simple ex-
traction. To further exemplify the safety and utility of this
process, a carboxylic acid API was safely manufactured on
>20 kg of an alkene (>40 mol) in high yield and purity. This
process will be detailed in a future publication.
(15) Though the conditions reported use 5% H2O–acetone, it notes
that MeCN is an adequate organic solvent.
(16) Caution: In addition to ozone’s inherent toxicity, bubbling
ozone/oxygen into a flammable organic solvent poses a fire
hazard.
(17) Solutions of heavier substrates (>500 g/mol) are inherently
more dilute in 20 volumes (mL/g) of solvent and are less exo-
thermic during the ozonolysis allowing the reaction to be con-
ducted at r.t.
Acknowledgment
(18) Secondary ozonide formation was measured by LC–MS, see
Supporting Information.
The author thanks Amgen research colleagues Matthew Bio, Seb
Caille, Jason Tedrow, Sheng Cui, and Chris Borths for support and
helpful discussions.
(19) Unlike some solvent systems, 10% H2O–MeCN does not turn
blue when saturated with ozone. Chemical indicators such as
Sudan III can also be used to determine the reaction end point.
See: Veysoglu, T.; Mitscher, L. A.; Swayze, J. K. Synthesis 1980,
807.
Supporting Information
(20) An EcoZone model EZ-1X ozone detector was positioned at the
reactor outlet. During the ozonolysis, no ozone was detected in
the head space until the alkene was consumed. This result was
repeatable with all substrates assuming a slow ozone delivery
rate (<2 scfh [standard cubic feet per hour]).
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560659.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
References and Notes
(21) In a number of substrates the peroxyacetals were detected by
LC–MS. Repeated injections of the sample showed the slow con-
version of the peroxyacetals to the aldehyde/hydrate over time.
(22) For the decomposition of ozone in water/organics, see:
Staehelle, J.; Hoigne, J. Environ. Sci. Technol. 1985, 19, 1206.
(23) Kürti, L.; Czakó, B. Strategic Applications of Named Reactions in
Organic Synthesis: Background and Detailed Mechanisms; Else-
vier Academic: Burlington, 2005, 354–356.
(24) Dalcanale, E.; Montanari, F. J. Org. Chem. 1986, 51, 567.
(25) Aging the reaction overnight with 3 equiv of sodium chlorite
resulted in 90–95% conversion.
(26) It is known that NaClO2 can be reduced with hypochlorite ions
and with hydrogen peroxide in acidic media. An additional
gaseous byproduct was formed detectable by the yellow color of
the nitrogen bubbler oil. The exact identity of this gas is not
known but is presumed to be Cl2 or ClO2, see ref. 23.
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of 3-Phenylpropanoic Acid (Table 1, Entry 1)
To a vial was added a solution of 4-phenyl-1-butene (1 mL, 0.88
g, 6.66 mmol, 1 equiv) dissolved in MeCN (15.8 mL, 18 mL/g)
and H2O (1.8 mL, 2 mL/g). The solution was cooled to 0 °C and
sparged with ozone at a rate of <2 scfh (standard cubic feet per
hour) while purging the head space of the vial with nitrogen.
Once ozone was detected in the head space, the ozone was
stopped and reaction completeness was confirmed by LC–MS. A
magnetic stir bar was added to the vial and the solution stirred
rapidly. An aqueous solution of NaClO2 (80 wt%, 3.01 g, 26.6
mmol, 4 equiv) in H2O (14 mL) was added portionwise to the
reaction while maintaining a internal reaction temp <15 °C. The
cold bath was removed from the reaction and the mixture
stirred for >12 h at r.t. under 1 atm of nitrogen. A solution of
NaHSO3 was made by dissolving Na2S2O5 (2.77 g, 14.58 mmol,
2.19 equiv) in H2O (14 mL). This solution was slowly added to
the reaction maintaining a internal temperature <35 °C and the
mixture stirred for 10 min. EtOAc (10 mL) was added to the
mixture, and the layers were separated. The aqueous layer was
extracted with EtOAc, the organic layers combined, dried over
MgSO4, filtered, and concentrated to provide a colorless oil
(0.95 g, 95% yield). 1H NMR (400 MHz, CDCl3): δ = 2.71 (t, J = 8.0
Hz, 2 H), 2.96 (t, J = 8.0 Hz, 2 H) 7.18–7.32 (m, 5 H), 10.30–11.30
(br s, 1 H).
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Richter, S. M.; Kallemeyn, J. M.; Robbins, T. A.; Kishore, V. Org.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 245–248