Chemo- and regioselective reductive deoxygenation of 1-en-4-yn-ols into 1,4-enynes through FeF3 and TfOH co-catalysis

Article abstract of DOI:10.1039/c5cc10518h

We report chemo- and regioselective direct reductive deoxygenation of 1-en-4-yn-3-ols into 1,4-enynes through FeF₃ and TfOH cooperative catalysis under NBSH-mediated conditions. Further, we show the efficient synthesis of a pharmaceutically significant 1,4-enyne. The present methodology can also be used for chemo- and regioselective direct deoxygenation of other alcohols.

Full text of DOI:10.1039/c5cc10518h

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Chemo- and regioselective reductive
deoxygenation of 1-en-4-yn-ols into 1,4-enynes
Cite this:DOI: 10.1039/c5cc10518h
through FeF3 and TfOH co-catalysis†
Received 23rd December 2015,
Accepted 29th March 2016
Zonglian Yang,a Rapolu Kiran Kumar,a Peiqiu Liao,a Zhaohong Liu,a Xingqi Lia and
Xihe Bi*ab
DOI: 10.1039/c5cc10518h
www.rsc.org/chemcomm
We report chemo- and regioselective direct reductive deoxygenation
of 1-en-4-yn-3-ols into 1,4-enynes through FeF3 and TfOH coopera-
tive catalysis under NBSH-mediated conditions. Further, we show the
efficient synthesis of a pharmaceutically significant 1,4-enyne. The
present methodology can also be used for chemo- and regioselec-
tive direct deoxygenation of other alcohols.
Deoxygenation of alcohol into hydrocarbons plays a significant role
in organic synthesis, especially in total synthesis and modification
of natural products.1 Thus far, alcohol deoxygenation has been
approached through various routes,2 which can be categorised into
a direct procedure with reductive deoxygenation of alcohols in a
single step2,3 or an indirect procedure with alcohols converted into
other functional groups prior to reduction.2,4 Direct reductive
dehydroxylation of a hydroxyl group under mild reaction conditions
is challenging due to the high dissociation energy of the C–O bond
and strong alkaline nature of the hydroxide ion (OHꢀ) generated
during the reaction. The most widely applied strategy for alcohol
dehydroxylation is ionic hydrogenation.5
In natural products, 1,4-enynes are important structural motifs;6
further, 1,4-enynes can be applied in organic synthesis.7 Moreover,
1,4-enynes such as hypoxoside (isolated from the corms of Hypoxis
plants),6 rooperol8a and (E)-1-methoxy-4-(5-phenylpent-4-en-1-yn-1-
yl)benzene8b exhibit remarkable anticancer activities against
oesophageal carcinoma cells. Thus, researchers have actively
investigated versatile methods for the synthesis of 1,4-enynes
over the past few decades.9–12 These methods are numerous
and include the direct synthesis of 1,4-enynes via palladium-
catalysed decarboxylation of allylic alkynoates (Fig. 1a);9a nickel-
catalysed addition of terminal alkynes to 1,3-dienes (Fig. 1b);9b,c
Fig. 1 Methods for synthesizing 1,4-enynes.
Wittig reaction with propargylic aldehydes (Fig. 1c);9d alkynylation carbonates9j with the appropriate alkynyl compounds (Fig. 1d);
of allylic halides,7a–c,9e allylic alcohols,9f,g allylic acetates9h,i or allylic coupling propargylic alcohols with alkenes,9k,l vinyl silanes9m or
vinyl iodides7d (Fig. 1e); enantioselective synthesis of 1,4-enynes8b,10
via double bond migration; alkynylation of allylic alcohols,8b allylic
a Department of Chemistry, Northeast Normal University, 5268 Renmin Street,
phosphates10a–c or allylic picolinates10d (Fig. 1f); miscellaneous
130024 Changchun, China. E-mail: bixh507@nenu.edu.cn
b State Key Laboratory of Elemento-Organic Chemistry, Nankai University,
methods;11 and indirect methods.7e,12 Nonetheless, the direct
alcohol deoxygenation approach to this kind of compounds has
300071 Tianjin, China
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5cc10518h not yet been established so far.
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Table 1 The control experimentsa
From our persistent efforts in the development of new reac-
tions based on alkyne functionalisation,13 we recently reported
Lewis and Brønsted acid-catalysed and 2-nitrobenzenesulfonyl-
hydrazide (NBSH)-mediated reductive deoxyallenylation of
31-propargylic alcohols (1) into a variety of mono-, di- and
trisubstituted allenes (2) (Fig. 1g).14 During this investigation,
we observed reductive dehydroxylation of 1,5-diphenylpent-1-
en-4-yn-3-ol (3a) into an 1,4-enyne, pent-1-en-4-yne-1,5-diyldibenzene
(4a), with a 95% isolated yield (Fig. 1h). The 1,5-diphenylpent-1-en-4-
yn-3-ol (3a) may have converted into an 1,4-enyne (4a) rather than an
allene (4a0) due to propargylic carbocation resonance rearrangement
into a benzylic carbocation for extra stability (see the plausible
mechanism; Fig. 2). To the best of our knowledge, using 1-en-4-yn-
ols as substrates to synthesise 1,4-enynes has not previously been
demonstrated.9–12 Because this method of reductive deoxygenation
of alcohols into hydrocarbons is novel in organic chemistry (vide
supra),1–5 and 1,4-enynes are important chemicals, we believe that
Entry
Difference from standard conditions
4a yieldb (%)
1
2
3
4
5
6
Without FeF3
No TfOH
Acetic acid (10 mol%) instead of TfOH
No NBSH
FeCl2 (20 mol%) instead of FeF3
FeCl3 (20 mol%) intead of FeF3
70
0
0
0
70
72
a
Reactions were performed on a 0.5 mmol scale of 3a in 3.0 mL nitro-
b
methane as solvent at rt for 1 h. Isolated yields.
investigation into reductive dehydroxylation of 1-en-4-yn-ols (3) into These two reactions indicate the significance of combining both
1,4-enynes (4) is significant in modern organic synthesis. FeF3 and TfOH. Replacing the TfOH with acetic acid, did not allow
Later, we performed the control experiments to check the any reaction to occur (entry 3). Likewise, the reaction without added
possible alterations to the standard reaction conditions (Table 1). NBSH did not afford the product (entry 4). Later, performing the
Performing the reaction without FeF3 sharply decreased the yield reactions in the presence of other iron salts like FeCl2 or FeCl3 in
of 3a to 70% (Table 1, entry 1) whereas, the reaction in the the place of FeF3, decreased the yield of 4a to 70–72% isolated
absence of TfOH, completely ceased the reaction (entry 2). yields (entries 5–6). With this, the optimal reaction conditions
for 0.5 mmol of 3a are NBSH (1.2 equiv.), FeF3 (20 mol%), TfOH
(10 mol%) in nitro-methane (3.0 mL) as solvent at RT.
Next, the substrate scope of the protocol was investigated
through the reaction of various 1-en-4-yn-ols (3b–m) (0.5 mmol)
with NBSH (0.6 mmol) in the presence of FeF3 (20 mol%) and
TfOH (10 mol%) in a CH3NO2 solvent under an N2 atmosphere
at room temperature (Scheme 1).
The 1-en-4-yn-ols, such as (E)-1-phenylpent-1-en-4-yn-3-ol (3b)
and the internal 1-en-4-yn-ol (3c), underwent reductive dihydrox-
ylation, as expected, to generate the corresponding 1,4-enynes
(4b–c) in 70–92% isolated yields. However, (E)-2-methyl-1,5-
diphenylpent-1-en-4-yn-3-ol (3d) produced a mixture containing
a direct deoxygenative 1,4-enyne (4d) and rearranged product
(4d0) at a 5 : 1 ratio and in 92% yield. The greater levels of 4d are
due to the greater stability of the benzylic carbocation. Specifi-
cally, the tertiary 1-en-4-yn-ols (3e–h) with different structural
motifs at propargylic positions, such as phenyl (3e–f), 2-naphthyl
(3g) and 2-thiophenyl (3h), participated in reductive dehydrox-
ylation under standard conditions without difficulty, thereby
producing the target 1,4-enynes (4e–h) in 57–89% isolated yields.
Notably, 1-en-4-yn-ols (3i–j) with strained alicyclic moieties,
such as cyclopropyl (3i) and cyclohexenyl (3j), also underwent
a smooth reductive dehydroxylation reaction, which formed
1,4-enynes (4i–j) at 75–85% isolated yields. Finally, 1-en-4-yn-
ols with a labile TMS-moiety (3k) and terminal 1-en-4-yn-ol (3l)
were reductively dehydroxylated into 1,4-enynes (4k–l) in 87–95%
isolated yields. From these data, the substrate scope of the
present protocol is quite broad, and both terminal and internal
1-en-4-yn-ols can be applied to FeF3 and TfOH cooperatively
catalysed and NBSH-mediated direct reductive dehydroxylation
of 1-en-4-yn-ols into the corresponding 1,4-enynes with moderate
Fig. 2 Plausible mechanism.
to excellent yields.
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Scheme 3 Synthesis of the pharmaceutically significant 1,4-enyne.
product 6c0 at a 1 : 2 ratio and in 57% yield. These products were
generated due to the greater stability of the p-methoxybenzylic
carbocation. Likewise allylic alcohol 5d underwent dehydroxylation
to afford the corresponding 6d as the product in 86% yield.
However, naphthyl alcohol (5e–f) deoxygenation produced relatively
low 1-ethyl-naphthalene (6e–f) yields.
Finally, a pharmaceutical application for this methodology
is demonstrated through the synthesis of (E)-1-methoxy-4-(5-
phenylpent-4-en-1-yn-1-yl)benzene, which is a 1,4-enyne with
anticancer properties against oesophageal carcinoma cells.8b
When (E)-5-(4-methoxyphenyl)-1-phenylpent-1-en-4-yn-3-ol (7)
(0.5 mmol) reacted with NBSH (1.2 equiv.) in the presence of
FeF3 (20 mol%) and TfOH (10 mol%) in a nitromethane solvent,
it successfully underwent reductive deoxygenation and efficiently
formed (E)-1-methoxy-4-(5-phenylpent-4-en-1-yn-1-yl)benzene (8)
at an 88% isolated yield (Scheme 3).
Based on the above results and our previous report,14 we
propose a plausible reaction mechanism for FeF3 and TfOH
cooperatively catalysed and NBSH-mediated reductive dehydroxyl-
Scheme 1 Synthesis of divergent 1,4-enynes from 1-en-4-yn-ols.
To examine the generality of this FeF3 and TfOH coopera- ation of 1-en-4-yn-3-ols (3) into 1,4-enynes (4) (Fig. 2a). The reaction
tively catalysed and the NBSH-mediated reductive dehydroxyla- may have been initiated by forming the superacid species
tion strategy, we further investigated the reaction using allylic [Fe(F)3(OTf)]H from FeF3 and TfOH; [Fe(F)3(OTf)]H reacts with
alcohols and naphthyl alcohols (Scheme 2). The allylic alcohols the –OH moiety of 1,5-diphenylpent-1-en-4-yn-3-ol (3a) to generate
5a and 5b bearing phenyl rings at the R1 and R2 positions a propargylic carbocation intermediate A. This propargylic carbo-
afforded 6a and 6b at 79% and 88% isolated yields, respectively. cation rearranges into a benzylic carbocation intermediate B
However, allylic alcohol 5c with different phenyl rings at the R1 through resonance; supporting this step, the formation of an
and R2 positions formed a small quantity of direct deoxyge- allene product 4a0 (Fig. 1h) is not observed. Furthermore,
nated product 6c and a larger quantity of the rearranged supporting carbocation resonance, a small quantity of 6c
is formed from 5c due to rearrangement of the stable
p-methoxybenzylic carbocation into an unstable p-nitrobenzylic
carbocation through resonance (Scheme 2). This intermediate B
reacts with NBSH to form the hydrazide intermediate C;
supporting this step, we isolated the hydrazide intermediate
in our previous investigation.14 Proton abstraction from the
hydrazide C by [Fe(F)3(OTf)]ꢀ instigates the decomposition of D
into 4a as the final product and completes the catalytic cycle
through regeneration of [Fe(F)3(OTf)]H whereas, in the case of
naphthyl alcohols such as 5e–5f reductive deoxygenation takes
place without the involvement of the carbocation rearrange-
ment step (Fig. 2b).
In conclusion, we have developed a method for chemo- and
regio-selective direct reductive deoxygenation of alcohols. This
investigation afforded a series of divergent 1,4-enynes. Further,
we show the reductive deoxygenation of other alcohols into
corresponding hydrocarbons and the efficient synthesis of
a pharmaceutically significant 1,4-enyne. The cost-effective
catalytic system and general practicality at an ambient tempera-
ture are additional appealing features illuminated through this
Scheme 2 Reductive deoxygenation of other alcoholic compounds.
investigation.
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This work was supported by the NSFC (21522202, 21372038),
the Ministry of Education of the People’s Republic of China
(NCET-13-0714), the Jilin Provincial Research Foundation for
Basic Research (20140519008JH), and the Fundamental Research
Funds for the Central Universities (2412015BJ005).
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