One-pot reductive cleavage of exo-olefin to methylene with a mild ozonolysis-Clemmensen reduction sequence

Article abstract of DOI:10.1016/j.tetlet.2010.06.102

A one-pot exo-olefin reductive cleavage was for the first time developed. The reaction could proceed under a mild condition avoiding the use of hazardous and expensive reagents. Meanwhile, a TMSCl-mediated Clemmensen reduction in alcoholic solvent was also examined.

Full text of DOI:10.1016/j.tetlet.2010.06.102

Tetrahedron Letters 51 (2010) 4534–4537
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One-pot reductive cleavage of exo-olefin to methylene with a mild
ozonolysis-Clemmensen reduction sequence
*
Shu Xu, Takayuki Toyama, Jun Nakamura, Hirokazu Arimoto
Graduate School of Life Sciences, Tohoku University, Katahira 2-1-1, Aoba, Sendai 980-8577, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-pot exo-olefin reductive cleavage was for the first time developed. The reaction could proceed
under a mild condition avoiding the use of hazardous and expensive reagents. Meanwhile, a TMSCl-
mediated Clemmensen reduction in alcoholic solvent was also examined.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 10 May 2010
Revised 14 June 2010
Accepted 21 June 2010
Available online 25 June 2010
Reductive cleavage of exo-olefin to methylene is an important
transformation in organic synthesis (Fig. 1).1 So far it can only be
achieved by multistep operations, for example, usually first oxida-
tive cleavage of the olefins to ketones and then deoxygenation to
the methylene groups. For the former oxidative olefin cleavage,
mild condition (activated zinc, saturated HCl in Et2O at 0 °C), which
avoids the utility of toxic Hg.3 Unfortunately, this work went lar-
gely unnoticed by our chemical community and further systematic
development of this methodology was not continued since then.
Therefore, in our research of the one-pot olefin reductive cleavage,
we started from the modification of the Yamamura method, be-
cause Et2O, the most successful solvent in the Yamamura condi-
tion, is not suitable for ozonolysis.
À
ozonolysis and Os=Ru-IO4 method are the two regular techniques.
Whereas, for the latter ketone carbonyl deoxygenation, many more
variety of methods have been applied, including Clemmensen
reduction2 and its Yamamura modification,3 thioacetal-based
reduction, Wolff–Kishner reduction and its Caglioti modification,4
and transformation to alcoholic derivatives followed by Barton–
McCombie deoxygenation or hydride reduction.
Step5 and atom economy6 are the current and future trends of
synthetic chemistry, which have received greater attention from
both industrial and academic communities. Thus, to avoid the
above-mentioned tedious procedures and hazardous expensive re-
agents, a one-pot atom-economic method is urgently desired for
the exo-olefin reductive cleavage. This promoted us to study on
the transformation by designing a cascade sequence with the com-
bination of ozonolysis and Clemmensen reduction, the two least
costly and most atom-economic conditions among the above.
Ozonolysis is a well-studied reaction, popularly applied in the or-
ganic synthesis field. Zinc metal is a textbook reductant for the
quench of the reactive ozone adduct. Also, so far zinc metal is
the only suitable reductant for the Clemmensen reduction. Thus
it may possibly be a good bridge to join the former oxidative olefin
cleavage and the latter carbonyl deoxygenation reactions.
H H
R
R'
R
R
R'
Yamamura-Clemmensen
O3 or
OsO4-NaIO4
Zn, HCl, Et2O, 0 ºC
Thioacetal-based
Ra-Ni
O
reduction
S
R
S
R'
acid catalyst
R'
EtOH, reflux
SH SH
Caglioti-
NH-Ts
Wolff-Kishner
N
NH2NH-Ts
reductant
reductant
R
R'
MeOH, reflux
S
NaH
CS2, MeI
Barton-
Clemmensen reduction2 is a historically important reaction.
However, because of its original harsh conditions (aqueous HCl, re-
flux) with toxic Hg reagent, it is seldom applied in the modern or-
ganic synthesis. In the late 1960s, Yamamura et al. developed an
excellent modification of the Clemmensen reduction with a very
OH
R'
McCombie
SMe
O
Bu3SnH, AIBN
R
R
R'
LiAlH4
TsCl, Py
OTs
R'
R
* Corresponding author. Tel.: +81 22 217 6201; fax: +81 22 217 6204.
E-mail address: arimoto@biochem.tohoku.ac.jp (H. Arimoto).
Figure 1. The reductive cleavage of exo-olefin to methylene and its typical
methodologies and conditions.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.102

S. Xu et al. / Tetrahedron Letters 51 (2010) 4534–4537
4535
Table 1
Chlorotrimethylsilane (TMSCl) with the combination of Zn in
dehydrated THF has been used for the reduction of carbonyl com-
pounds to alkenes.7 In a specific case, this condition was reported
to give the Clemmensen products in low yields (ꢀ30%).8 We found
that with some proton sources as the additive, TMSCl–Zn in fact
could be an excellent reagent pair for the Clemmensen reduction,
even without pre-activation of the zinc metal. A screen of solvents
was carried out with cholestan-3-one 1a as the substrate and the
results are summarized in Table 1.9 With H2O as the proton source,
in aprotic solvents such as dichloromethane (DCM), isopropyl iso-
butylate (iPrOC(O)iPr), EtOAc, and N,N-dimethylacetamide (DMA),
the alkene byproduct 3 could always be detected. In THF (entry
5), the desired compound 2a was almost the sole product with
good isolated yield. Unfortunately, we failed to apply THF as the
common solvent also for ozonolysis, because, as one of the typical
ether-type solvent, its oxidative decomposition could not be ig-
nored as expected.
Finally, alcoholic solvents were found to be excellent for our
TMSCl-mediated Clemmensen reduction. The byproduct 3 could
only be detected in trace amount, if any. However, in MeOH (entry
6), the reaction was very slow. Even after 6 h, the starting material
1a still remained in large amount. This might be due to the ketone–
methyl acetal equilibrium, which retarded the desired deoxygen-
ation. Though as far as we tried, in this compound case the corre-
sponding methyl acetal could never be directly observed, the
existence of acetal was partly supported when iPrOH was applied
(entry 7). In this case, formation of the hindered isopropyl acetal
is expected to be difficult. As a result, in accordance with the
Screen of solvents for deoxygenation of 1a to 2a
H
H
H
H
H
H
H
3
3
H
TMSCl (0.64M)
3
O
Zn / TMSCl = 2:1
H
H
H
0 º
C
1a
3
2a
Entry Solvent
Condition
Ratio of 2a and 3a Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
DCM
H2O (3 equiv), 3 h
H2O (3 equiv), 0.5 h
H2O (3 equiv), 1 h
3:5c
4:1
n.d.
n.d.
n.d.
n.d.
82
iPrOC(O)iPr
EtOAc
20:1
DMA
THF
H2O (6 equiv), 10 hd,e 50:1
H2O (3 equiv), 1 h
6 h
>50:1
>50:1f
>50:1
>50:1
>50:1
>50:1
>50:1
>50:1
>50:1
>50:1
MeOH
iPrOH
n.d.
79
1.5 h
iPrOH
H2O (4.5 equiv), 3 hg
73
86
84
81
86
84
79
iPrOHh
tAmylOH
3 hg
6 hd
iPrOH/DCM (1:1) 2.5 hg
iPrOH/DCM (3:1) 3 h
EtOH/DCM (3:1)
5 hd
MeOH/DCM (3:1) 8.5 hi
a
b
c
d
e
f
Determined by the integration in 1H NMR of crude products.
Isolated yield, n.d. = not determined.
Determined by GC–MS.
1.27 M of TMSCl was used.
The reaction was conducted at room temperature.
Compound 1a could not be fully consumed with a ratio of 1:4 to compound 2a
determined by GC–MS.
g
0.93 M of TMSCl was used.
Dehydrated solvent was used.
1.87 M of TMSCl was used.
h
i
Table 2
Clemmensen reduction with various ketones using TMSCl–Zn in alcoholic solventsa
Entry
Ketone
Product
Solvent
Yieldb (%)
O
H
H
1
MeOH/DCM 1 h
82
H
H
H
H
HO
H
HO
2b
H
1b
O
H
H
2
3
MeOH/DCM 1 h
EtOH/DCM 1 h
94
90
H
H
H
H
MOMO
H
MOMO
2c
H
1c
O
H
H
H
H
H
H
TBDPSO
H
H
TBDPSO
H
2d
H
1d
OMe
O
O
O
OMe
O
N
O
N
4
iPrOH/DCM 1.5 h
77
O
2e
1e
5
6
MeOH/DCM 0.5 h
98c
28c
1f
2f
O
Ph
Ph
iPrOH/DCM 3 h
2g
1g
a
Typical procedure: To ketone (0.20 mmol) in alcohol/DCM (3:1, 20 mL), were added zinc powder (20 mmol) and dropwise TMSCl (20 mmol) under ice-water bath. The
reaction mixture was then stirred at 0 °C for the given reaction time. NaHCO3 (24 mmol) was added. After stirring for 5 min, the reaction mixture was filtered and the filtrate
was concentrated. The residue was partitioned with CHCl3 and saturated aqueous NH4Cl. The organic layer was dried with Na2SO4, filtered, concentrated, and purified by
silica gel column chromatography to afford the pure product.
b
Isolated yield.
Determined by GC–MS.
c

4536
S. Xu et al. / Tetrahedron Letters 51 (2010) 4534–4537
Table 3
One-pot reductive cleavage of olefin with various substratesa
R
R
R
º
O3, alcohol / DCM (3:1), -78 C
H
H
O
H
0 ºC
then Zn, TMSCl, -78 ºC to 0 ºC
R'
R'
R'
4
Entry
1
Olefin
Product
Solvent
Yieldb (%)
H
H
H
iPrOH/DCM 0.5 hc
87
H
H
H
H
H
H
4a
2a
H
H
H
2
3
MeOH/DCM 1 h
75
72
H
O
H
H
O
H
HO
O
HO
H
2b
4b
OMe
OMe
H
H
O
N
N
iPrOH/DCM 0.75 h
2e
2f
4e
4
MeOH/DCM 1 h
86d
4f
a
Typical procedure: O3 was passed through a solution of olefin (0.20 mmol) in alcohol/DCM (3:1, 20 mL) at À78 °C. After the olefin was fully consumed by TLC check,
excess O3 was removed by a stream of Ar for 10 min. At À78 °C, zinc powder (20 mmol) was added followed by dropwise TMSCl (20 mmol). Then the reaction temperature
was gradually increased to 0 °C and stirred at 0 °C for the given reaction time. The same workup procedure as in Table 2 was followed to afford the pure product.
b
Isolated yield.
Zn/TMSCl = 2:1, TMSCl (0.33 M).
Determined by GC–MS.
c
d
hypothesis, 1a was fully consumed within 1.5 h and 2a could be
isolated in good yield. In tert-Amyl alcohol (entry 10), 1a could also
be fully consumed, but the reaction became slower. Next, since the
ozonolysis is usually conducted at low temperature such as À78 °C,
for the solubility reason,10 the mixed solvent system was studied.
From entries 11–14, it was found that with DCM as the co-solvent,
common alcoholic solvents all gave good yields without the loss of
the selectivity.
the one-pot olefin reductive cleavage was studied. The results
are summarized in Table 3.9 Good to excellent yields were
obtained with multi-functionalized substrates. In the case of com-
pound 4e (entry 3), one-pot 72% yield was obtained compared to
the previous three-step 49% result,11 which showed the feasibility
of our method in the complex natural product synthesis. In entry
4, an internal olefin 4f could also be cleaved and reduced
efficiently.
The established condition was then applied to various carbonyl
compounds to prove the scope and generality. As shown in Table
2,9 good to excellent yields were obtained with different types of
ketones by the appropriate choice of the alcoholic solvent. For
compound 1d (entry 3), the reaction did not complete with iPrOH
as the co-solvent. Instead, in MeOH, though the reaction was fast,
the TBDPS was partly deprotected. Finally, EtOH proved to be the
suitable solvent and gave an excellent yield. Compound 1e (entry
4) is an important synthetic intermediate in our total synthesis
of pinnaic acid, a bioactive marine alkaloid.11 The substrate had
been shown to be sensitive to many deoxygenation conditions de-
scribed in Figure 1. Only modest yield (60%) had been obtained
with the two-step Caglioti-modified Wolff–Kishner reduction.4
This time, by the application of our TMSCl-mediated Clemmensen
condition with iPrOH, 77% yield of 2e was achieved with simpler
operations. Interestingly, unlike compound 1a, when using MeOH
as the co-solvent, in this case, the methyl acetal12 was confirmed
and could be isolated from the reaction system, which was perhaps
because of the more stability of cyclopentaone acetal than that of
cyclohexanone.
In summary, a one-pot exo-olefin reductive cleavage was for the
first time developed. This reaction could proceed under a mild
condition avoiding the use of hazardous and expensive reagents.
During the research process, a TMSCl-mediated Clemmensen
reduction in alcoholic solvent was also examined.
Acknowledgments
We are grateful for the financial support from Grant-in-Aid for
Scientific Research (21310136 and 21221009) from JSPS, the Ueha-
ra memorial foundation, and G-COE program for Molecular Com-
plex Chemistry at Tohoku University from MEXT, Japan.
References and notes
1. Richard, C. L. In Comprehensive Organic Transformation, 2nd ed.; Wiley-VCH:
New York, 1999.
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React. 1975, 22, 401–422.
3. (a) Yamamura, S.; Ueda, S.; Hirata, Y. Chem. Commun. 1967, 1049–1050; (b)
Toda, M.; Hayashi, M.; Hirata, Y.; Yamamura, S. Bull. Chem. Soc. Jpn. 1972, 45,
264–266; (c) Yamamura, S.; Toda, M.; Hirata, Y. Org. Synth. Coll. 1988, 6, 289–
292.
With the successful development of the TMSCl-mediated
Clemmensen reduction, combination of it with ozonolysis for

S. Xu et al. / Tetrahedron Letters 51 (2010) 4534–4537
4537
4. (a) Hutchins, R. O.; Milewski, C. A.; Maryanoff, B. E. J. Am. Chem. Soc. 1973, 95,
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Caglioti, L. Tetrahedron 1966, 22, 487–493.
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9. All the reagents and solvents mentioned in this Letter were used as received
from commercial suppliers.
10. At À78 °C, the substrate was poorly soluble in alcoholic solvent.
11. Xu, S.; Arimoto, H.; Uemura, D. Angew. Chem., Int. Ed. 2007, 46, 5746–5749.
12.
O
OMe
H
N
O
OMe
OMe
7. (a) Motherwell, W. B. J. Chem. Soc., Chem. Commun. 1973, 935–937; For a
review, see: (b) Motherwell, W. B. Aldrichim. Acta 1992, 25, 71–80.
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