Flow Dehydration and Hydrogenation of Allylic Alcohols: Application to the Waste-Free Synthesis of Pristane

Article abstract of DOI:10.1002/ejoc.201700072

Hydroxy-substituted sulfonic acid functionalized silica (HO-SAS) in combination with THF containing a small amount of water as a solvent proved to be a reliable system for the dehydration of allylic alcohols. This process generally caused dehydration within 1 min through a column reactor charged with HO-SAS. The flow dehydration was sequenced by flow hydrogenation, which resulted in the synthesis of pristane. A scalable flow synthesis of pristane was successfully performed and afforded 10 g of pristane after an operation of 2 h. We also performed dehydration and hydrogenation by using a mixed column of HO-SAS and 10 % Pd/C.

Full text of DOI:10.1002/ejoc.201700072

A Journal of
Accepted Article
Title: Flow Dehydration and Hydrogenation of Allylic Alcohols;
Application to the Waste-Free Synthesis of Pristane
Authors: Akihiro Furuta, Yuki Hirobe, Takahide Fukuyama, Ilhyong
Ryu, Yoshiyuki Manabe, and Koichi Fukase
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700072
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10.1002/ejoc.201700072
European Journal of Organic Chemistry
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Flow Dehydration and Hydrogenation of Allylic Alcohols;
Application to the Waste-Free Synthesis of Pristane
Akihiro Furuta,[a] Yuki Hirobe, [a] Takahide Fukuyama,*[a] Ilhyong Ryu, [a, b] Yoshiyuki Manabe, [c] and
Koichi Fukase[c]
Abstract: Hydroxy-substituted sulfonic acid-functionalized silica
(HO-SAS) in combination with THF containing a small amount of
water as a solvent proved to be a reliable system for the dehydration
of allylic alcohols. This process generally causes dehydration within
1 min through a column reactor charged with HO-SAS. The flow
dehydration was sequenced via flow hydrogenation that resulted in
the synthesis of pristane. Scalable flow synthesis of pristane was
successfully carried out, and turned 10 grams of pristane after
operation for 2 h. We also performed dehydration and hydrogenation
using the mixed column of HO-SAS and 10% Pd/C.
charged with a HO-SAS catalyst with THF as a solvent. In an
important development, the protocol was successfully applied to
the consecutive flow synthesis of pristane via sequential
dehydration and hydrogenation.[13]
The dehydration of alcohols shows promise as a method to
prepare alkenes and Brønsted acids, such as sulfuric acid and
p-toluenesulfonic acid, are often used as catalysts for many
transformations.[1] In a homogeneous reaction system using a
batch flask, two issues are always confronted: (i) accumulated
water deactivates acid catalysts; and, (ii) after the reaction, acids
must be neutralized and removed as waste (Scheme 1, type 1).
A flow dehydration system using a supported acid catalyst can,
however, override these issues (Scheme 1, type 2). Thus, when
water formed via dehydration is washed out by a solvent, an
active acid catalyst is maintained, and no need to neutralize the
acid after completion of the reaction. Since silica gel has a large
surface area and high thermal stability, sulfonic acid
functionalized silica (SAS) was developed as a solid acid
[2]
catalyst
and tested for its ability to dehydration of sugar,[3]
glycerol,[4] nitro alcohols,[5] and chromanols.[6] Whereas those
studies used a batch system, Scott, Dumesic, and co-workers
reported a SAS-catalyzed dehydration of fructose using a
packed-bed reactor. With a flow system, unfortunately, a large
quantity of water is required as a cosolvent to dissolve fructose,
which naturally deactivates SAS.[3f]
Scheme 1. Comparison of the features of batch and flow dehydration systems
catalyzed by solid acids.
By comparison with butyric acid, β-hydroxy butyric acid is
stronger in terms of the pKa values,[7] and we speculated that a
stainless steel column
4.0 mm i.d., 50 or 150 mm long
flow system using sulfonic acid functionalized silica with a β-
BPR
[8,9]
hydroxyl function (HO-SAS)
would serve as a far better
Brønsted acid catalyst for the dehydration of alcohols (Scheme
2). Here, we report a clean and fast-flow dehydration of allylic
alcohols by using the combination of a column reactor
pump
oil bath
[10-12]
OH
O
O
O
SiO2
[a]
A. Furuta, Y. Hirobe, Prof. T. Fukuyama, Prof. I. Ryu
Department of Chemistry, Graduate School of Science, Osaka
Osaka Prefecture University
Si
O
SO3H
HO-SAS
Sakai, Osaka, 599-8531 (Japan)
E-mail: fukuyama@c.s.osakafu-u.ac.jp
http://www.c.s.osakafu-u.ac.jp/~ryu/?lang=en
Prof. I. Ryu
Department of Applied Chemistry
National Chiao Tung University
Hsinchu (Taiwan)
Dr. Y. Manabe, Prof. K. Fukase
Department of Chemistry, Graduate School of Science
Osaka University
Toyonaka, Osaka, 560-0043 (Japan)
Scheme 2. Schematic illustration of a HO-SAS-charged column reactor.
[b]
[c]
HO-SAS (340 mg, pore size of 7 μm) was packed into a
stainless steel column (4.0 mm i.d. x 50 mm long), to which
back-pressure regulator (40 psi) was connected through
stainless tube (Scheme 2). For a model reaction, we studied
dehydration of three types of alcohols (Scheme 3). When a 0.17
M of THF solution of 1 was fed into a column reactor immersed
in an oil bath (90 °C), the dehydration reaction of 1 proceeded
Supporting information for this article is given via a link at the end of
the document.
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with 30 seconds of residence time to give 1-phenylpentadiene 2
in 80% yield. Similarly the dehydration of α-cumyl alcohol 3 and
styryl ethanol 5 gave the corresponding dehydrated products 4
and 6 in good yields. Simple secondary and tertiary alcohols
such as 2-decanol, 2-methyl-2-undecanol were not dehydrated
under the same conditions.
Then, we turned our attention to an application of the
dehydration protocol in the synthesis of pristane (2,6,10,14-
tetramethylpentadecane), which is a natural saturated branched
alkane obtained from a Basking Shark.[14] Pristane is known to
induce autoimmune diseases in rodents and is now being widely
used as an adjuvant for monoclonal antibody production.15 In
vitro pristane synthesis from farnesol typically consists of four
steps: (i) oxidation of farnesol to give an aldehyde, (ii) alkylation
by Grignard reaction to give alcohol 7, (iii) dehydration of 7 by p-
TsOH to give tetraene 8, and (iv) hydrogenation of 8 to give
pristane 9.[15] In 2007, the Fukase group reported the synthesis
of pristane via flow dehydration. Though quite smooth, the flow
dehydration protocol employed a stoichiometric amount of p-
TsOH, which required a neutralization workup and a subsequent
separation of the product from
the resultant organic salts by
extractive separation. Thus, we thought that a waste-free
dehydration would be possible by using a HO-SAS-charged
column reactor.
The results are summarized in Table 1. The initial experiment
used a batch dehydration of 7 (0.85 mmol) in THF and
proceeded in 4 h under reflux conditions with HO-SAS (340 mg)
to give the pristane precursor 8, and a subsequent batch
hydrogenation gave the desired pristane 9 in a 75% yield, but
the purity was as low as 66% due to competing cationic
cyclization (entry 1). We next examined flow dehydration, which
returned a 92% yield of 9 with an improved purity of 76% (entry
2). We then examined additives to reduce the side products via
cationic cyclization. The addition of 2% of methanol (entry 3)
and acetic acid (entry 4) in THF did not improve the purity of 9.
It was interesting, however, that the addition of 2-5 % of water
caused a significant increase in purity (88-91%) (entries 5-7) at
the cost of a slightly lower level of conversion. The use of a
larger amount of HO-SAS (1,020 mg) with a longer column (4.0
mm i.d. x 150 mm long) compensated for the reaction rate,
which gave and 87% yield of 9 while maintaining a good level of
purity (92%) (entry 8). The precise role of water in the effect on
purity remains unclear at this stage. We can speculate, however,
that water present in the vicinity of the sulfonic acid functional
group would promote a quick deprotonation of the cationic
species prior to intramolecular addition. For comparison, we
tested two different pore sizes of SAS with no hydroxyl group
(entries 9 and 10) and found that the HO-SAS was most
Scheme 3. Dehydration of alcohols with HO-SAS. Conditions: Alcohol (0.86
mmol), THF (5 mL), HO-SAS (340 mg) packed column (4.0 mm i.d. x 50 mm
long), temp. 90 °C, residence time 30 s.
We then examined the time profile of the dehydration of 1
(Scheme 4). The flow reaction eluted during the first 2 min was
discarded, and the reaction mixture was collected in each 15
min. The catalyst could be used for 90 min without any
detectable loss in catalytic activity.
effective in terms of efficiency and selectivity.
We then
examined the gram-scale synthesis of the pristane by changing
the syringe pump to an HPLC pump. After operation for 2 h and
a subsequent batch hydrogenation, we obtained 10 grams of
pristane 9, which amounted to an 80% isolated yield with 87%
purity after column chromatography on silica gel (entry 11). This
was accomplished with the use of 1.4 mol% of the acid catalyst,
which was based on calculation.
Scheme 4. Time profile for the dehydration of 1 with HO-SAS. Conditions:
Alcohol (12.8 mmol), THF (75 mL), HO-SAS (340 mg) packed column (4.0 mm
i.d. x 50 mm long), temp. 90 °C, residence time 30 s. Yield was determined by
GC analysis using n-hexadecane as an internal standard.
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10.1002/ejoc.201700072
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therefore, for this solvent system, we established an extended
residence time (3.2 s) by using a longer packed column (4.0 mm
i.d. x 50 mm long), which gave a 95% yield of reduced alkane 11.
Finally, we created a flow production system of pristane 9 for the
combined flow dehydration and hydrogenation of 8, which used
the same solvent system of THF plus water. The hydrogenation
of polyene 8 was completed within 3.2 seconds of residence
time to give pristane 9 in 80% via a two-step yield with 87%
purity. Since hydrogen gas would not affect the dehydration
step, we also examined the use of a column wherein both HO-
SAS and Pd on carbon were mixed (Scheme 5). This also
worked well and contributed to a further simplification of the
protocol.
Table 1. Flow dehydration of hydroxyl triene 7 and a reductive conversion to
pristine 9 [a]
Table 2. Hydrogenation of squalane 10 [a]
10% Pd/C
10
H2 gas
11
[a] Allyl alcohol 7 (0.85 mmol), solvent (5 mL), HO-SAS (340 or 1,020 mg) a
packed column (4.0 mm i.d. x 50 mm or 150 mm long), 90 °C, 30 s of
residence time. After dehydration, the crude reaction mixture was
hydrogenated without purification. [b] Total yields of pristane
9 and
inseparable by-products. [c] Determined by GC. [d] Batch reaction: allyl alcohol
7 (0.85 mmol), THF (5 mL), HO-SAS (340 mg), reflux, 4 h. [e] SAS-6 and
SAS-15 with pore sizes of 6 μm and 15 μm were used. [f] Operation time: 2 h.
With the satisfactory flow dehydration of 7 to 8 in hand, next we
pursued a flow catalytic hydrogenation of 8 to 9. As a model, we
employed the flow hydrogenation of squalene 10 as a polyene
using a column reactor filled with 10% Pd/C (Table 2). Thus, 10
was introduced to a micromixer with a 0.5 μm i.d. and a flow rate
of 0.15 mL/min via an HPLC pump. Hydrogen gas was
introduced to the micromixer via a mass flow controller with a
flow rate of 9.8 mL/min. The reaction mixture was passed
through a 10% Pd/C packed-bed reactor (4.0 mm i.d. x 10 mm
long) connected to a back pressure regulator (20 psi). The flow
hydrogenation of 10 to give 11 was completed in 0.9 s of
residence time using AcOEt as a solvent (entry 1). Using THF
with 3% of water, the reaction of 10 was slightly sluggish, and,
[a] Squalene 10 (0.5 mmol), solvent (5 mL), 10% Pd/C (29 or 180 mg) packed
column (4.0 mm i.d. x 10 or 50 mm long). [b] Isolated yield.
In summary, the HO-SAS-catalyzed flow dehydration of allylic
alcohols worked quite well when THF was used as the solvent.
The flow system was applied to the synthesis of a pristane
precursor, in which the addition of a small amount of water was
effective in supressing side reactions to provide cyclization by-
products. This two-step flow synthesis of pristane via a
sequence of consecutive dehydration/hydrogenation was
successfully carried out using a one-column double catalyst
system, in which neither separation of the catalysts nor
switching of the solvent was necessary.
mass flow controller
HO-SAS (450 mg)
10% Pd/C (450 mg)
BPR
H2
90 °C, 30 s
pump
OH
7
0.17 M in THF, H2O (3%)
9
pristane
76%a, purity 91%
a Total yields of 9 and by-products
Scheme 5. Flow synthesis of pristane 9 from 7 using a mixed catalyst
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Acknowledgements
This work was supported by JSPS KAKENHI (No. 15H05850)
in Middle Molecular Strategy.
Keywords: microreactors • allyl alcohols • solid acid •
dehydration • hydrogenation
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
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Text for Table of Contents
Author(s), Corresponding Author(s)*
Page No. – Page No.
Title
Layout 2:
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mixed catalyst
Akihiro Furuta, Yuki Hirobe, Takahide
Fukuyama,* Ilhyong Ryu, Yoshiyuki
Manabe, and Koichi Fukase
OH
O
SiO2
Si
O
SO3H
O
O
OH
Pd/C
Page No. – Page No.
pristane
Flow Dehydration and Hydrogenation
of Allylic Alcohols; Application to the
Waste-Free Synthesis of Pristane
dehydration
and hydrogenation
H2 gas
90 °C, 30 s
Hydroxy-substituted sulfonic acid-functionalized silica (HO-SAS) in combination
with THF containing a small amount of water as a solvent proved to be a reliable
system for the dehydration of allylic alcohols. This process generally causes
dehydration within 1 min through a column reactor charged with HO-SAS. The flow
dehydration was sequenced via flow hydrogenation that resulted in the synthesis of
pristane.
Key word : packed-bed reactor,
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