Triphenylphosphine Oxide-Catalyzed Selective α,β-Reduction of Conjugated Polyunsaturated Ketones

Article abstract of DOI:10.1055/s-0037-1611537

The scope of the triphenylphosphine oxide-catalyzed reduction of conjugated polyunsaturated ketones using trichlorosilane as the reducing reagent has been examined. In all cases studied, the α,β-C=C double bond was selectively reduced to a C-C single bond while all other reducible functional groups remained unchanged. This reaction was applied to a large variety of conjugated dienones, a trienone, and a tetraenone. Additionally, a tandem one-pot Wittig/conjugate-reduction reaction sequence was developed to produce γ,δ-unsaturated ketones directly from simple building blocks. In these reactions the byproduct of the Wittig reaction served as the catalyst for the reduction reaction. This strategy was then used in the synthesis of naturally occurring moth pheromones to demonstrate its utility in the context of natural-product synthesis.

Full text of DOI:10.1055/s-0037-1611537

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
letter
A
en
X. Xia et al.
Letter
Synlett
Triphenylphosphine Oxide-Catalyzed Selective ,-Reduction of
Conjugated Polyunsaturated Ketones
O
O
Xuanshu Xia
Zhiqi Lao
15 examples
91–100% yield
R1
R2
R1
R2
O
O
O
Patrick H. Toy*
0
0
0
0-
0
0
0
1-6
3
2
2-0
1
2
1
Ph3P=O (catalyst)
Cl3SiH
96% yield
O
Department of Chemistry, The University of Hong Kong,
Pokfulam Road, Hong Kong, P. R. of China
phtoy@hku.hk
highly selective
organocatalytic
process
95% yield
O
O
2 examples
>67% yield
R1
R1
R2
R2
Received: 05.03.2019
Accepted after revision: 04.04.2019
Published online: 24.04.2019
edge, the only reported general methods for the selective
,-reduction of conjugated polyunsaturated ketones in-
volve the use of catecholborane,4 Stryker’s reagent,5 or a
catalytic InCl3/NaBH4 reaction system.6 Additionally, a
B(C6F5)3/poly(methylhydrosiloxane) reaction system that
might be highly selective has been reported, but it was ap-
plied to only a single polyunsaturated ketone substrate and
a related ester–nitrile substrate.7 Finally, a Ru-catalyzed
process was found to be relatively unselective in the single
example studied.8 Consequently, whereas methods for se-
lective metal-catalyzed 1,4-9 and 1,6-conjugate additions10
of carbon nucleophiles to conjugated polyunsaturated ke-
tones are relatively widely known, highly selective organo-
catalytic methods for 1,4-conjugate hydride addition for
double-bond reduction are virtually unknown. Here we re-
port a study of the substrate scope of the HSiCl3-mediated
reduction of conjugated polyunsaturated ketones catalyzed
by oxide 1 and its application to the synthesis of a series of
naturally occurring moth pheromones.
DOI: 10.1055/s-0037-1611527; Art ID: st-2019-w0132-l
Abstract The scope of the triphenylphosphine oxide-catalyzed reduc-
tion of conjugated polyunsaturated ketones using trichlorosilane as the
reducing reagent has been examined. In all cases studied, the ,-C=C
double bond was selectively reduced to a C–C single bond while all oth-
er reducible functional groups remained unchanged. This reaction was
applied to a large variety of conjugated dienones, a trienone, and a tet-
raenone. Additionally, a tandem one-pot Wittig/conjugate-reduction
reaction sequence was developed to produce ,-unsaturated ketones
directly from simple building blocks. In these reactions the byproduct
of the Wittig reaction served as the catalyst for the reduction reaction.
This strategy was then used in the synthesis of naturally occurring moth
pheromones to demonstrate its utility in the context of natural-product
synthesis.
Key words triphenylphosphine oxide, trichlorosilane, reduction, Lewis
base, organocatalysis, pheromones
Several years ago, Nakajima and co-workers reported
the selective 1,4-conjugate reduction of ,-unsaturated ke-
tones catalyzed by Lewis bases such as HMPA or triphenyl-
phosphine oxide (1) with HSiCl3 as the reducing reagent.1
Interestingly, one of the examples they reported was the se-
lective reduction of conjugated dienone 2a to unsaturated
ketone 3a (Scheme 1). Because the ,-unsaturated ketone
structural motif appears in a variety of natural products, we
were intrigued by this reaction and curious about its sub-
strate scope. This exact transformation had been previously
reported by others using different reaction conditions
[Pd(PPh3)4/ZnCl2/Ph2SiH2 or Hantzsch ester/SiO2 ] that
were found not to be generally selective across a range of
conjugated dienone substrates; we therefore thought that
the selective conversion of 2a into 3a might simply be due
to steric interference by the methyl groups. To our knowl-
O
O
HMPA (0.2 equiv)
Cl3SiH (2.0 equiv)
CH2Cl2, 0 °C
3a
94% yield
2a
Scheme 1 Selective reduction of conjugated dienone 2a to 3a
The conjugated diene substrates for our study 2b–p
were prepared in a straightforward manner as outlined in
Scheme 2,11 with the phosphine-catalyzed isomerization of
alkynones to trans,trans-dienones as the key transforma-
tion.12 Specifically, terminal alkynes 4 were deprotonated
with BuLi and then treated with an aldehyde to produce the
corresponding secondary alcohols 5 after workup. These
alcohols were oxidized with MnO2 to afford the alkynone
2
3
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

B
X. Xia et al.
Letter
Synlett
isomerization products 6, which, in turn, were treated with
catalytic amounts of Ph3P in toluene at elevated tempera-
ture to afford 2b–p with high stereochemical purity.
With the conjugated polyunsaturated ketone substrates
2b–r in hand, we began our studies of the selective reduc-
tion reaction by using the originally reported reaction con-
ditions as a starting point.1 Whereas the original report de-
scribed the use of HMPA as the nucleophilic Lewis base cat-
alyst at 0 °C, we chose to use 1 as the catalyst at –78 °C, on
the basis of our previous research on related reductive aldol
reactions.13 Gratifyingly, by using these conditions for the
reduction of 2b in CH2Cl2we obtained 3b in 95% yield after
purification (Table 1, entry 1).14 Application of the same re-
duction conditions to aryl ketones 2c–i, including some
with potentially acid-sensitive and/or reducible groups, af-
forded the corresponding ketones 3c–i in excellent yields
(entries 2–8). Heteroaromatic ketones 2j and 2k were also
selectively reduced (entries 9 and 10). Phenyl ketones 2l–n,
containing potentially acid-sensitive and/or reducible
groups, also proved to be good substrates, affording ketones
3l–n in excellent yields (entries 11–13). Methyl ketones 2o
and 2p were cleanly converted into 3o and 3p, respectively
(entries 14 and 15). Finally, trienone 2q and tetraenone 2r
were selectively reduced to 3q and 3r, respectively (entries
16 and 17). In all cases the selectivity of the reactions per-
mitted very simple purification of the products by silica gel
chromatography. Therefore, overall, it seems that the
Cl3SiH-mediated reduction of conjugated polyunsaturated
ketones catalyzed by 1 is a highly selective and efficient
method for reduction of ,-C=C double bonds.
OH
1. nBuLi
THF, –78 °C
2. R1CHO
H
MnO2
R1
CH2Cl2, rt
R2
R2
4
5
O
Ph3P
toluene, 50 °C
O
R1
R1
R2
R2
2b–p
6
Scheme 2 Synthesis of conjugated polyunsaturated ketone substrates
2b–p
Trieneone 2q was synthesized by a similar route, except
that methyl chloroformate was used instead of an aldehyde
to convert the deprotonated alkyne 4 into the alkynoate 7
(Scheme 3). This product was isomerized, reduced, and
then oxidized to give the corresponding dienal 8. Finally, di-
enal 8 was treated with phosphorane 9 to afford 2q. The
synthesis of tetraenone 2r involved the reaction of dienal 8
with phosphorane 10 to afford trienoate 11. This, in turn,
was reduced and oxidized to afford trienal 12. Finally, treat-
ment of 12 with phosphorane 9 afforded 2r.
1. nBuLi
THF, –78 °C
O
H
2. ClC(O)OMe
MeO
nBu
Table 1 Selective Reduction of Conjugated Polyunsaturated Ketonesa
nBu
4
7
1 (0.2 equiv)
Cl3SiH (2.0 equiv)
CH2Cl2, –78 °C
1. Ph3P, toluene, 50 °C
2. DIBALH, CH2Cl2, 0 °C
3. MnO2, CH2Cl2, rt
O
O
O
H
R'
R"
R'
R"
8
2
3
Ph3P
O
Entry
1
Product
Isolated yield (%)
95
O
9
O
CHCl3, reflux
2q
32% overall yield
3b
Ph3P
O
O
EtO
O
10
8
2
93
CHCl3, reflux
EtO
11
3c
1. DIBALH, CH2Cl2, 0 °C
2. MnO2, CH2Cl2, rt
O
O
H
3
4
96
91
12
TBSO
3d
9
O
CHCl3, reflux
O
2r
19% overall yield
NC
3e
Scheme 3 Synthesis of trienone 2q and tetraenone 2r
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

C
X. Xia et al.
Letter
Synlett
Table 1 (continued)
O
O
1. Ph3P (1.05 equiv), DIPEA (1.5 equiv)
CH2Cl2, 45 °C
X
R1
R1
R2
Entry
Product
Isolated yield (%)
100
13
2. Cl3SiH (2.0 equiv), –78 °C
3
O
(1.05 equiv)
+
O
5
O
O
Ph3P
N
H
+
1
O
R1
R2
H
R2
R1
3f
14
2
15
(1.0 equiv)
O
O
Scheme 4 One-pot synthesis of ,-unsaturated ketones
nBu
nBu
6
7
92
96
O
3g
Having established the general applicability of the re-
duction reaction, we next examined the possibility of using
it in a one-pot multistep reaction system for the direct syn-
thesis of ,-unsaturated ketones from simple building
blocks. This idea was based on the work reported by Zhou
and co-workers, in which they performed Wittig reactions
to form enones, followed directly by a Cl3SiH-mediated re-
duction reactions catalyzed by oxide 1, formed as a byprod-
uct of the first reaction.15,16 Our idea is summarized in
Scheme 4. Specifically, we planned to mix an -halo ketone
13 with an ,-unsaturated aldehyde 14 in the presence of
Ph3P and DIPEA to generate a phosphorane intermediate 15
in situ, which would, in turn, react with 14 to generate a di-
enone 2 and oxide 1. Once the formation of 2 was complete,
Cl3SiH would be added and 1 would catalyze the reduction
of 2 to form ,-unsaturated ketone 3. Gratifyingly, by using
-halo ketones 13a–c and ,-unsaturated aldehydes 14a
and 14b, we were able to synthesize ,-unsaturated ke-
tones 3s–u directly in one-pot procedures with good overall
yield, especially considering the number of sequential reac-
tions involved (Figure 1).17
O
Br
3h
O
MeO
nBu
8
100
MeO
OMe
3i
O
N
nBu
9
100
98
3j
O
O
nBu
10
3k
O
11
12
13
14
96
99
95
99
Ph
3l
OBn
OTHP
OAll
O
O
O
Br
O
Br
Cl
Ph
Ph
3m
13a
Br
13c
13b
O
O
O
Ph
3n
H
Ph
H
14a
14b
O
O
Ph
O
3o
Ph
Ph
O
Br
3s
O
O
68% yield
3t
82% yield
15
98
O
3p
Ph
O
3u
54% yield
16
17
96
95
3q
Figure 1 One-pot reaction starting materials and products
O
3r
a Reaction conditions: 1 (0.2 mmol), 2 (1.0 mmol), Cl3SiH (2.0 mmol),
CH2Cl2 (5 mL), –78 °C.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

D
X. Xia et al.
Letter
Synlett
Finally, to showcase the utility of the reduction reaction
in the context of natural-product synthesis, we targeted the
moth pheromones 16a and 16b (Scheme 5).18 The common
starting material for both syntheses was phosphorane 9,
which was deprotonated and treated with an 1-bromohep-
tane (17a) or 1-bromooctane (17b) to introduce what
would eventually become the fully saturated side chains of
16a and 16b, respectively. The resulting phosphoranes 18a
and 18b were not purified and were treated directly with
non-2-ynal (19)19 to perform a Wittig reaction. In a manner
similar to the procedure used for the synthesis of 3s–u, the
resulting alkene products were not isolated but, instead,
Cl3SiH was added directly to the reaction mixture to reduce
the newly formed C=C double bonds in situ to form unsatu-
rated ketones 20a and 20b. Finally, reduction of the alkyne
groups to the corresponding (Z)-alkene groups completed
the syntheses of 16a and 16b in excellent overall yields
from 9.11
Ph
P
Ph
O
Ph
H
O
Cl3
Si
R'
R"
Figure 2 Possible reaction transition state
the latter substrates was studied to demonstrate the utility
of this synthetic method in the context of natural-product
synthesis through the synthesis of moth pheromones 16a
and 16b. We are currently exploring the utility of this
method in other contexts for the selective synthesis of in-
teresting organic molecules, and we will report our results
in due course.
Funding Information
1. nBuLi, THF, –78 °C
2. 17a or 17b
Ph3P
This research was supported financially by the University of Hong
Kong and the Research Grants Council of the Hong Kong S. A. R., P. R.
O
9
R
of China (Project No. 17305915).
R
esearc
h
Grants
C
o
u
n
c
i
l,
U
n
i
v
ersityGrants
C
o
m
m
i
te
e
(1
7
3
0
5
9
1
5)
18a: R = (CH2)7Me
18b: R = (CH2)8Me
O
Supporting Information
H2, Pd/BaSO4
quinoline
1. 19, CH2Cl2, rt
2. Cl3SiH, –78 °C
R
EtOAc-hexane, rt
Supporting information for this article is available online at
5
https://doi.org/10.1055/s-0037-1611527.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orit
n
gInformati
o
n
20a: R = (CH2)7Me
20b: R = (CH2)8Me
References and Notes
O
(1) Sugiura, M.; Sato, N.; Kotani, S.; Nakajima, M. Chem. Commun.
2008, 4309.
16a (67% overall yield)
(2) Keinan, E.; Greenspoon, N. J. Am. Chem. Soc. 1986, 108, 7314.
(3) Fujii, M.; Nakamura, K.; Yasui, S.; Oka, S.; Ohno, A. Bull. Chem.
Soc. Jpn. 1987, 60, 2423.
(4) Kraft, P.; Ahlin, J. S. E.; Büchel, M.; Sutter, P. Synthesis 2012, 44,
2985.
O
16b (70% overall yield)
Scheme 5 Synthesis of moth pheromones 16a and 16b
(5) Kraft, P.; Jordi, S.; Denizot, N.; Felker, I. Eur. J. Org. Chem. 2014,
554.
(6) Ranu, B. C.; Samanta, S. J. Org. Chem. 2003, 68, 7130.
(7) Chandrasekhar, S.; Chandrashekar, G.; Reddy, M. S.; Srihari, P.
Org. Biomol. Chem. 2006, 4, 1650.
(8) Li, W.; Wu, X.-F. Eur. J. Org. Chem. 2015, 331.
(9) Gan, K.; Ng, J. S.; Sadeer, A.; Pullarkat, S. A. Synlett 2016, 26, 254.
(10) Silva, E. M. P.; Silva, A. M. S. Synthesis 2012, 44, 3109.
(11) See Supporting Information for details.
(12) For a review, see: Kwong, C. K.-W.; Fu, M. Y.; Sze-Lok Lam, C.;
Toy, P. H. Synthesis 2008, 40, 2307.
(13) (a) Lu, J.; Toy, P. H. Chem. Asian J. 2011, 6, 2251. (b) Teng, Y.; Lu,
J.; Toy, P. H. Chem. Asian J. 2012, 7, 351.
With regards to the mechanism of this selective reduc-
tion reaction, the sum total of our results with a wide vari-
ety of reaction substrates supports the notion originally
proposed by Nakajima and co-workers that a six-mem-
bered cyclic transition state might be involved. Specifically,
they proposed that the silicon atom of the reducing reagent
simultaneously interacts with the oxygen atom of the sub-
strate and the Lewis base catalyst, thereby permitting deliv-
ery of hydride selectively at the -position (Figure 2).
In summary we have demonstrated that the previously
reported Cl3SiH-mediated 1,4-reduction of conjugated poly-
unsaturated enones catalyzed by oxide 1 is applicable to a
wide range of substrates to produce ,-unsaturated ketone
products. These reaction conditions are compatible with a
wide range of potentially reducible functional groups, and
even a trienone (2q), a tetraenone (2r), and alkynenones
generated in situ were selectively reduced. The reduction of
(14) Enones 3b–r (Table 1); General Procedure
A solution of the appropriate diene 2b–r (1.0 mmol) and
Ph3P=O (1) (0.2 mmol) in anhyd CH2Cl2 (5 mL) was stirred under
N2 and cooled to –78 °C. Cl3SiH (2.0 mmol) was added, and stir-
ring was continued for 2 h more. The mixture was then allowed
to warm to rt and the volatiles were removed under a stream of
air. Sat. aq Na2CO3 (20 mL) and CH2Cl2 were added, and the
resulting suspension was stirred for 30 min. The layers were
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

E
X. Xia et al.
Letter
Synlett
separated and the aqueous layer was extracted with additional
CH2Cl2 (3 × 20 mL). The combined organic layers were dried
(Na2SO4), filtered, and concentrated under reduced pressure.
The crude product was purified by chromatography [silica gel,
EtOAc–hexane (10:90)].
(17) Aryl Enones 3s–u; General Procedure
A mixture of the appropriate aryl ketone 13a–c (2.1 mmol),
enone 14a or 14b (2.0 mmol), Ph3P (2.1 mmol), and DIPEA (3.0
mmol) in anhyd CH2Cl2 (10 mL) was stirred under N2 and
refluxed. When the Wittig reaction was completed (TLC), the
mixture was cooled to –78 °C and Cl3SiH (4.0 mmol was added.
The mixture was stirred for 2 h more and then warmed to rt.
After 2 h, the volatiles were removed under a stream of air. Sat.
aq Na2CO3 (20 mL) and CH2Cl2 (20 mL) were added, and the
resulting suspension was stirred for 30 min. The layers were
separated and the aqueous later was extracted with additional
CH2Cl2 (3 × 20 mL). The combined organic layers were dried
(Na2SO4), filtered, and concentrated under reduced pressure.
The crude product was purified by chromatography [silica gel,
EtOAc–hexane (10:90)].
(4E)-1-(2-Naphthyl)hex-4-en-1-one (3b)
Clear oil; yield: 213 mg (95%). 1H NMR (400 MHz, CDCl3):
 = 1.61 (d, J = 3.8 Hz, 3 H), 2.41–2.46 (m, 2 H), 3.04 (t, J = 7.3 Hz,
2 H), 5.46–5.48 (m, 2 H), 7.39 (t, J = 7.7 Hz, 1 H), 7.46 (t, J = 7.7
Hz, 1 H), 7.53 (t, J = 7.7 Hz, 1 H), 7.76 (d, J = 7.1 Hz, 1 H), 7.79 (d,
J = 8.2 Hz, 1 H), 7.88 (d, J = 8.2 Hz, 1 H), 8.57 (d, J = 8.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 17.9, 27.6, 41.9, 124.3, 125.8,
126.1, 126.6, 127.3, 127.7, 128.4, 129.6, 130.1, 132.3, 133.9,
136.1, 204.2. HRMS (El-MS): m/z calcd for C16H16O: 224.1201;
found: 224.1190.
(15) (a) Cao, J.-J.; Zhou, F.; Zhou, J. Angew. Chem. Int. Ed. 2010, 49,
4976. (b) Chen, L.; Shi, T.-D.; Zhou, J. Chem. Asian J. 2013, 8, 556.
(c) Chen, L.; Du, Y.; Zeng, X.-P.; Shi, T.-D.; Zhou, F.; Zhou, J. Org.
Lett. 2015, 17, 1557.
(16) For other recent examples of the ‘use of a byproduct in a subse-
quent reaction’ concept, see: (a) Zhu, F.; Xu, P.-W.; Zhou, F.;
Want, C.-H.; Zhou, J. Org. Lett. 2015, 17, 972. (b) Zhou, X.-P.; Cao,
Z.-Y.; Wang, X.; Chen, L.; Zhou, F.; Zhu, F.; Wang, C.-H.; Zhou, J. J.
Am. Chem. Soc. 2016, 138, 416. (c) Gao, X.-T.; Gan, C.-C.; Liu, X.-
Y.; Zhou, F.; Wu, H.-H.; Zhou, J. ACS Catal. 2017, 7, 8588. (d) Liu,
Y.-L.; Yin, X.-P.; Zhou, J. Chin. J. Chem. 2018, 36, 321. (e) Hu, X.-
S.; Yu, J.-S.; Gong, Y.; Zhou, J. J. Fluorine Chem. 2019, 219, 106.
(5E)-6-Phenylhex-5-en-2-one (3s)
Clear oil; yield: 237 mg (68%). 1H NMR (400 MHz, CDCl3):  =
2.16 (s, 3 H), 2.46–2.51 (m, 2 H), 2.58–2.63 (m, 2 H), 6.19 (dt, J1 =
15.8, J2 = 6.7 Hz, 1 H), 6.40 (d, J = 15.8 Hz, 1 H), 7.16–7.21 (m, 1
H), 7.24–7.34 (m, 4 H). 13C NMR (100 MHz, CDCl3):  = 27.2,
30.2, 43.3, 126.1, 127.2, 128.6, 128.9, 130.9, 137.5, 208.2. HRMS
(El-MS): m/z calcd for C12H14O: 174.1045; found: 174.1031.
(18) (a) Tamaki, Y.; Honma, K.; Kawasaki, K. Appl. Entomol. Zool.
1977, 12, 60. (b) Wenkert, E.; Ferreira, V. F.; Michelotti, E. L.;
Tingoli, M. J. Org. Chem. 1985, 50, 719. (c) Yamamoto, I.; Tanaka,
S.; Fujimoto, T.; Ohta, K. J. Org. Chem. 1989, 54, 747.
(19) Lapointe, G.; Schlenk, K.; Renaud, P. Org. Lett. 2011, 13, 4774.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E